2-Naphthylacetic acid derivatives

ABSTRACT

2-Naphthyl acetic acid derivatives and the corresponding amides, esters, hydroxamic acids and addition salts thereof, optionally substituted at the α-position on the acetic acid moiety and/or at position 6 and/or at positions 1, 4, 7 or 8 on the naphthyl ring and optionally saturated at positions 3 and 4, are anti-inflammatory, analgesic, anti-pyretic and anti-pruritic agents. A pharmaceutical method of effecting treatment of inflammation, pain, pyrexia and pruritus by the administration of naphthyl acetic acid derivatives. A pharmaceutical composition for use in the treatment of the above maladies comprising a naphthyl acetic acid derivative.

This is a division of application Serial No. 558,874, now U.S. Pat. No.4,001,301, filed Mar. 17, 1975, which in turn is a division ofapplication Serial No. 195,875, filed Nov. 4, 1971, now U.S. 3,896,157,which in turn is a division of application Serial No. 694,771, filedDec. 7, 1967, now abandoned, which is a continuation-in-part of U.S.application 608,997 filed Jan. 13, 1967 now abandoned.

This invention relates to novel compositions useful asanti-inflammatory, analgesic, anti-pyretic and anti-pruritic agents. Italso relates to novel methods for treating conditions marked byinflammation, pain, pyrexia, and pruritus. It further relates to novelcompounds which are thus useful and to methods for their preparation, aswell as to certain novel intermediates thereof.

The present compounds are derivatives of 2-naphthylacetic acid, acompound which can be represented by the formula: ##STR1##

The arabic numerals and the alpha symbol indicate the positions usedherein in the nomenclature of 2-naphthylacetic acid derivatives.

The present invention more particularly pertains to a method ofeffecting treatment of inflammation, pain, pyrexia, and pruritus, aswell as associative conditions thereof, by administering an effectivequantity of a 2-naphthylacetic acid derivative as hereinafter defined orthe corresponding amide, ester, hydroxamic acid or addition saltthereof, which salt is derived from a pharmaceutically acceptablenon-toxic base.

These thus useful 2-naphthylacetic acid derivatives can be representedby the following formulas: ##STR2## wherein each of R⁶ (at position 1,4, 7 or 8) and R¹⁹ (at position 1, 7 or 8) is alkyl, trifluoromethyl,fluoro, chloro, hydroxy, conventional hydrolyzable ester, oxyether orthioether;

R⁸ is alkyl, fluoro, chloro, hydroxy, conventional hydrolyzable ester,oxyether or thioether;

each of R⁹ (at position 1, 4, 7 or 8) and R²⁰ (at position 1, 7 or 8) isalkyl, fluoro, chloro, hydroxy, conventional hydrolyzable ester,oxyether or thioether, provided that when R⁸ is hydroxy, oxyether orthioether, R⁹ or R²⁰ is the identical group or alkyl, fluoro, chloro orconventional hydrolyzable ester; provided that when one of R⁹ or R²⁰ ishydroxy, oxyether or thioether, R⁸ is the identical group or alkyl,fluoro, chloro, or conventional hydrolyzable ester;

each of R¹² and R¹⁵ (at position 1 or 4) is hydroxy, oxyether orthioether;

each of R¹³ (at position 1 or 4) and R¹⁴ is alkoxy or alkylthio,provided when R¹² or R¹⁵ is alkoxy or alkylthio, R¹³ or R¹⁴ respectivelyis a different alkoxy or alkylthio group;

one of R¹⁶ and R¹⁷ is hydrogen, the other being hydrogen, methyl, ethyl,difluoromethyl, fluoro or chloro; or

R¹⁶ and R¹⁷ taken together are alkylidene, halomethylene or ethylene;

R¹⁸ is hydrogen, alkyl, cycloalkyl, trifluoromethyl, hydroxymethyl,alkoxymethyl, vinyl, ethynyl, fluoro, chloro, hydroxy, conventionalhydrolyzable ester, oxyether, thioether, formyl, carboxy,alkoxycarbonyl, acetyl, cyano or aryl;

R²¹ is hydrogen, alkyl, cycloalkyl, trifluoromethyl, fluoro, chloro,hydroxy, conventional hydrolyzable ester, oxyether, thioether or aryl;and

the corresponding amides, esters, hydroxamic acids and pharmaceuticallyacceptable addition salts thereof.

Several classes of novel naphthylacetic acid derivatives of formulasI-VIII include those of the following formulas: ##STR3## wherein one ofR¹ and R² is hydrogen and the other is difluoromethyl, fluoro or chloro;or

R¹ and R² taken together are alkylidene, halomethylene, or ethylene;

R³ is trifluoromethyl, conventional hydrolyzable ester, difluoromethoxy,alkoxymethyloxy, 4'-alkoxytetrahydropyran-4'-yloxy,tetrahydrofuran-2'-yloxy, tetrahydropyran-2'-yloxy, or thioether;

R⁴ is cycloalkyl, hydroxymethyl, alkoxymethyl, trifluoromethyl, vinyl,ethynyl, a conventional hydrolyzable ester, alkoxymethyloxy,alkylthiomethylthio, difluoromethoxy, alkoxymethylthio,alkylthiomethyloxy, difluoromethylthio, formyl, carboxy, alkoxycarbonyl,acetyl, cyano, or aryl;

each of R⁵ (at position 4, 7 or 8) and R⁶ (at position 1, 4, 7 or 8) isalkyl, trifluoromethyl, fluoro, chloro, hydroxy, conventionalhydrolyzable ester, oxyether or thioether; provided that R⁵ (when atposition 7) is other than alkyl;

R⁷ is alkyl, cycloalkyl, hydroxymethyl, alkoxymethyl, trifluoromethyl,vinyl, ethynyl, fluoro, chloro, hydroxy, conventional hydrolyzableester, oxyether, thioether, formyl, carboxy, alkoxycarbonyl, acetyl,cyano or aryl;

each of R⁸ and R⁹ (at positions 1, 4, 7 or 8) is alkyl, fluoro, chloro,hydroxy, conventional hydrolyzable ester, oxyether or thioether;provided that when one of R⁸ or R⁹ is hydroxy, oxyether or thioether,the other is the identical group or alkyl, fluoro, chloro orconventional hydrolyzable ester;

one of R¹⁰ and R¹¹ is hydrogen, the other being methyl, ethyl,difluoromethyl, fluoro or chloro; or

R¹⁰ and R¹¹ taken together are alkylidene, halomethylene, or ethylene;provided that when one of R¹⁰ or R¹¹ is methyl or ethyl, R⁶ (when atposition 1 or 7) is other than alkyl; and

the corresponding amides, esters, hydroxamic acids and pharmaceuticallyacceptable addition salts thereof.

By the terms which define an "alkyl" grouping are meant lower molecularweight, branched, or straight chain hydrocarbon groups of six or lesscarbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,tertbutyl, pentyl, hexyl, and the like. By the term "cycloalkyl" ismeant cyclic hydrocarbon groups of three to seven carbon atoms, such ascyclopropyl, cyclopentyl, cyclohexyl, and the like.

By the term "alkoxy" is intended a straight or branched chainhydrocarbon ether group of six or less carbon atoms, including methoxy,ethoxy, 2-propoxy, butoxy, 3-pentoxy, and the like.

By the terms which define an "alkoxymethyloxy" grouping are meantmethylether groups substituted with one alkoxy group; typicalalkoxymethyloxy groups include methoxymethyloxy, ethoxymethyloxy,isopropoxymethyloxy, and the like.

By the term "alkylthio" is intended straight or branched chainhydrocarbon thioether groups of six or less carbon atoms, includingmethylthio, ethylthio, propylthio, 2-propylthio, 2-butylthio,pentylthio, 3-hexylthio, and the like.

The term "alkylthiomethyloxy" as used herein denotes methylether groupssubstituted with an alkylthio group; typical alkylthiomethyloxy groupsinclude methylthiomethyloxy, 2-propylthiomethyloxy, pentylthiomethyloxy,and the like.

The term "alkylthiomethylthio" as used herein denotes methylthio ethergroups substituted with an alkylthio group, includingmethylthiomethylthio, ethylthiomethylthio, and the like.

By the terms which define an "alkoxymethylthio" grouping are meantmethylthio ether groups substituted with one alkoxy group, such asmethoxymethylthio, ethoxymethylthio, 2-propoxymethylthio, and the like.

By the term "aryl" is intended unsubstituted and p-mono substitutedphenyl derivatives, such as phenyl, p-tolyl, p-fluorophenyl,p-chlorophenyl, p-hydroxyphenyl, p-methoxyphenyl, p-ethylphenyl, and thelike.

By the term "halomethylene" is meant mono- or dihalo-methylene groupswherein halo is fluoro or chloro. The preferred halomethylenes includefluoromethylene, difluoromethylene, fluorochloromethylene, andchloromethylene.

The term "conventional hydrolyzable ester" as used herein denotes thosehydrolyzable ester groups conventionally employed in the art, preferablythose derived from hydrocarbon carboxylic acids or their salts. The term"hydrocarbon carboxylic acid" defines both substituted and unsubstitutedhydrocarbon carboxylic acids. These acids can be completely saturated orpossess varying degrees of unsaturation (including aromatic), can be ofstraight chain, branched chain, or cyclic structure and, preferably,contain from one to twelve carbon atoms. In addition, they can besubstituted by functional groups, for example, hydroxy, alkoxycontaining up to six carbon atoms, acyloxy containing up to twelvecarbon atoms, nitro, amino, halogeno and the like, attached to thehydrocarbon backbone chain. Typical conventional hydrolyzable estersthus included within the scope of the term and the instant invention areacetate, propionate, butyrate, valerate, caproate, enanthate, caprylate,pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate,phenylacetate, diphenylacetate, diethylacetate, trimethylacetate,t-butylacetate, trimethylhexanoate, methylneopentylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate,methoxyacetate, hemisuccinate, hemiadipate, hemi-β,β-dimethylglutartate,acetoxyacetate, 2-chloro-4-nitrobenzoate, aminoacetate,diethylaminoacetate, piperidinoacetate, β-chloropropionate,trichloroacetate, β-chlorobutyrate, and the like.

The term "oxyether" as used herein denotes those ether groupsconventionally employed in the art, preferably those derived from normalchain, branched chain, aromatic hydrocarbons and oxo heterocyclichydrocarbons. The term "hydrocarbon" defines both saturated andunsaturated hydrocarbons. Those designated hydrocarbons are optionallysubstituted with groups such as hydroxy, alkoxy, halo, alkylthio, andthe like. Preferably the hydrocarbons contain from one to twelve carbonatoms. Typical oxyethers thus include alkoxy, difluoromethoxy,alkoxymethyloxy, alkylthiomethyloxy, tetrahydrofuran-2'-yloxy,tetrahydropyran-2'-yloxy, and 4'-alkoxytetrahydropyran-4'-yloxy.

The term "thioether" as used herein denotes those ether groupsconventionally employed in the art, preferably those derived from normalchain, branched chain, cyclic and aromatic hydrocarbons. The term"hydrocarbon" defines both substituted and unsubstituted hydrocarbons.These hydrocarbons are optionally substituted with groups such ashydroxy, alkoxy, alkylthio, halo and the like. Preferably thehydrocarbons contain from 1 to 12 carbon atoms. Typical thioethers thusinclude alkylthio, difluoromethylthio, alkoxymethylthio,alkylthiomethylthio, and the like.

Also included within the scope of the present invention are thecorresponding amides, esters hydroxamic acids, and addition salts of thepresent 2-naphthylacetic acids.

In the preferred embodiment of this invention, the amides, esters,hydroxamic acids, or addition salts of the present 2-naphthylacetic acidderivatives are the preferred derivatives when the 2-naphthylacetic acidderivatives are substituted with tetrahydrofuran-2'-yloxy,tetrahydropyran-2'-yloxy, 4'-alkoxytetrahydropyran-4'-yloxy,alkylmethylenedioxy, alkylthiomethyleneoxy, alkoxymethylthio, oralkylthiomethylthio.

The amides of the present novel compounds are derived from conventionalbases, such as ammonia, methylamine, ethylamine, methylethylamine,dimethylamine, diethylamine, pyrrolidine, piperidine, piperazine,N-ethylpiperazine, morpholine, di(methoxymethylene)amine,isopropylamine, aniline, N-methyl-N-cyclopentylamine, and the like. Theamides are prepared by conventional means known to the art, for example,by treating the naphthylacetic acid derivatives with thionylchloride,phosphorus pentachloride, and the like, and then treating the resultingacid chloride of the naphthylacetic acid derivative with an excess ofammonia or an amine.

The esters are also prepared by conventional techniques, such as bypreparing the acid chloride of the 2-naphthylacetic acid derivative andthen allowing the acid chloride to react with an alkanol, such asmethanol, ethanol, and the like; or by treating the 2-naphthylaceticacid derivative with a diazoalkane, for example, diazomethane,diazoethane, and the like; or with an alkanol of 1 to 12 carbon atoms,for example, methanol, ethanol, butanol, or 3-pentanol, in the presenceof an acid catalyst such as borontrifluoride, p-toluenesulfonic acid, orthe like.

The hydroxamic acid derivatives are prepared by treating the2-naphthylacetic acid ester derivatives with hydroxylamine (usually asthe hydrochloride salt) in the presence of base, such as sodiummethoxide, in an alkanol solvent, such as methanol, ethanol, and thelike.

The addition salts are prepared by conventional techniques frompharmaceutically acceptable non-toxic bases, including metal salts suchas sodium, potassium, calcium, aluminum, and the like, as well asorganic amine salts, such as triethylamine, 2-dimethylamino ethanol,2-diethylamino ethanol, lysine, arginine, histidine, caffeine, procaine,N-ethylpiperidine, hydrabamine, and the like.

Of the compounds of formulas I-VIII of this invention (defined above),the preferred derivatives are those wherein each of R⁶ (at position 1,4, 7 or 8) and R¹⁹ (at position 1, 7 or 8) is fluoro, chloro, methyl,ethyl, isopropyl, methoxy, methoxymethyloxy, difluoromethoxy,4'-methoxytetrahydropyran-4'-yloxy, methylthio, difluoromethylthio, ormethoxymethylthio;

each of R⁸, R⁹ (at position 1, 4, 7 or 8) and R²⁰ (at position 1, 7 or8) is fluoro, chloro, methyl, ethyl, isopropyl, methoxy,methoxymethyloxy, difluoromethoxy, 4'-methoxytetrahydropyran-4'-yloxy,methylthio, difluoromethylthio, or methoxymethylthio; provided that whenone of R⁸ and R⁹ or one of R⁸ and R²⁰ is hydroxy, oxyether or thioether,the other is the identical group, or methyl, ethyl, isopropyl, fluoro orchloro;

each of R¹², R¹³ (at position 1 or 4), R¹⁴ and R¹⁵ (at position 1 or 4)is methoxy, difluoromethoxy, methoxymethyloxy,4'-methoxytetrahydropyran-4'-yloxy, methylthio, difluoromethylthio ormethoxymethylthio; provided that R¹³ or R¹⁴ is a different substituentthan R¹² or R¹⁵ respectively;

one of R¹⁶ and R¹⁷ is hydrogen, the other being hydrogen, methyl ordifluoromethyl; or

R¹⁶ and R¹⁷ taken together are methylene or difluoromethylene;

R¹⁸ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl,vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy,difluoromethoxy, 4'-methoxytetrahydropyran-4'-yloxy, methylthio,methoxymethylthio, or a difluoromethylthio;

R²¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl,methoxy, methoxymethyloxy, difluoromethoxy,4'-methoxytetrahydropyran-4'-yloxy, methylthio, methoxymethylthio, ordifluoromethylthio; and

the corresponding amides, esters, hydroxamic acids and addition saltsthereof.

When one of R¹ and R² or R¹⁰ and R¹¹ or R¹⁶ and R¹⁷ is methyl, ethyl,difluoromethyl, fluoro or chloro, the present 2-naphthylacetic acidderivatives have an asymmetric carbon atom, the α-carbon atom of theacetic acid moiety. Accordingly, these compounds can exist asenantiomorphs. Each of the optical isomers of the present2-naphthylacetic acid derivatives is included within the presentinvention. In some instances, one enantiomorph exhibits greateranti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity,than the other enantiomorph.

The present 2-naphthylacetic acid derivatives that exist asenantiomorphs can be administered as mixtures of enantiomorphs or asresolved enantiomorphs.

The optical isomers can be resolved by conventional means, such asselective biological degradation; or by the preparation ofdiastereo-isomer salts of the 2-naphthylacetic acid derivatives with analkaloid, such as cinchonidine, and the separation of thediastereo-isomers by fractional crystallization. The separateddiastereo-isomer salts are acid cleaved to yield the respective opticalisomers of the 2-naphthylacetic acid derivatives.

The above compounds have high therapeutic value in the treatment ofvarious inflammatory conditions, such as of the skin, eyes, respiratorytract, bones, and internal organs, contact dermatitis, allergicreactions, and rheumatoid arthritis. In those cases in which the aboveconditions include pain, pyrexia, and pruritus, coupled with theinflammation, the instant compounds ae useful for relief of theseassociative conditions as well as the principal condition. The instantcompounds are in addition, however, useful for treating pain, pyrexia,pruritus, and other syndromes thereof per se, such as those arising frombone fracture, toothache, bacterial and virus infection, contact withpoisonous material, neuralgia, neuritis, lacerations, contusions,abrasions, and the like.

The preferred manner of oral administration provides the use of aconvenient daily dosage regimen which can be adjusted according to thedegree of affliction. Generally, a daily dose of from 0.1 mg. to 20 mg.of the active compound per kilogram of body weight is employed. Mostconditions respond to treatment comprising a dosage level in the orderof 1 mg. to 5 mg. per kilogram or body weight per day. For such oraladministration, a pharmaceutically acceptable non-toxic composition isformed by the incorporation of any of the normally employed excipients.These compositions take the form of solutions, suspensions, tablets,pills, capsules, powders, sustained release formulations, and the like.

In addition, these compounds can be administered inconjunction withother medicinal agents depending upon the specific condition beingtreated.

Thus, for example, a measure of anti-inflammatory activity according tothe carrageenin induced edema assay of Winter et al., Proceedings of theSociety for Experimental Biology and Medicine III, 544 (1962) shows6-ethyl-2-naphthylacetic acid and 6-methoxy-2-naphthyl-α-methylaceticacid to have three times and greater than six times the activity ofphenylbutazone, respectively. Similar standard assays to measureanalgesic and anti-pyretic activities show6-methoxy-2-naphthyl-α-methylacetic acid to be three times and seventimes the activity of aspirin in these two respective categories.

The above compounds of the present invention can be readily preparedfrom known starting compounds.

One such method by which they can be prepared involves the reaction ofan unsubstituted or substituted naphthalene with acetyl chloride innitrobenzene in the presence of about three molar equivalents ofaluminum chloride to afford the corresponding 2-acetylnaphthalenederivative. The resulting derivative is heated with morpholine in thepresence of sulfur at 150° C; the resulting product is refluxed withconcentrated hydrochloric acid to furnish the corresponding2-naphthylacetic acid derivative.

The naphthalenes that are used in the above process can be illustratedby the following formulas: ##STR4## wherein R⁸, R⁹ and R¹⁸ are asdefined above.

The naphthalenes of formulas A and B are known to the art. Moreover,they can be prepared by conventional means. For example,1,2-dimethoxybenzene is treated with succinic anhydride and aluminumchloride in a hydrocarbon solvent to afford4-(3',4'-dimethoxyphenyl)-4-oxobutanoic acid. This is reduced bytreatment with sodium borohydride, hydrogenolyzed by treating withpalladium charcoal catalyst and hydrogen to furnish4-(3',4'-dimethoxyphenyl) butanoic acid. The corresponding acid chlorideis prepared such as by teatment with thionyl chloride, and the acidchloride is treated with aluminum chloride to afford6,7-dimethoxy-1-tetralone. The tetralone is reduced and hydrogenolyzedby the means described above to furnish 6,7-dimethoxytetralin which isdehydrogenated by treating with palladium charcoal catalyst to afford2,3-dimethoxy naphthalene. By utilizing 1-methyl-3-fluorobenzene in theabove process, 6-methyl-8-fluoro-4-tetralone and6-fluoro-8-methyl-4-tetralone (as intermediates) and 1-methyl-3-fluoronaphthalene and 1-fluoro-3-methyl naphthalene are prepared. The mixtureof naphthalenes are separated by conventional means, such as vacuumdistillation.

2-Alkyl, 2-cycloalkyl, or 2-aryl substituted naphthalenes, thenaphthalenes of formula A wherein R¹⁸ is alkyl or aryl, can be preparedfrom 2-tetralone by treating the latter with an equivalent of an alkyl,cycloalkyl or aryl magnesium bromide in an ether to obtain thecorresponding 2-alkyl-, 2-cycloalkyl-, or 2-aryl-3,4-dihydronaphthalenewhich is dehydrogenated by heating with palladium charcoal catalyst toafford the corresponding 2-alkyl, 2-cycloalkyl, or 2-aryl naphthalene.

2-Vinyl naphthalenes are prepared by refluxing 2-ethyl naphthalenes witha molar equivalent of N-bromosuccinimide in a halohydrocarbon solvent,such as chloroform, methylene chloride, dichloroethane,carbontetrachloride, 1,4-dichlorobutane, chlorobenzene, chloroethane,chlorocyclohexane, dichlorobenzene, and the like, in light and in thepresence of a trace amount of peroxide, such as benzoyl peroxide,t-butylperoxide, peroxyacctic acid, and the like, to afford thecorresponding 2-(α-bromoethyl)naphthalene. The latter isdehydrobrominated by treating with lithium carbonate indimethylformamide to afford 2-vinylnaphthalene.

2-Ethynylnaphthalene is prepared from 2-vinylnaphthalene by brominatingthe latter in a halo hydrocarbon solvent and then debrominating theresulting 2-(α,β-dibromoethyl)naphthalene by conventional means, such asby treatment with sodium amide in liquid ammonia, to furnish the2-ethynylnaphthalene.

2-Cyclopropylnaphthalene is prepared from 2-vinylnaphthalene byrefluxing with diiodomethane in the presence of zinc: copper couple.

2-Cyclobutylnaphthalene is prepared from 2-naphthylmagnesium bromide bytreating the latter with cyclobutanone to furnish2-(1'-hydroxycyclobutyl)-naphthalene, which is hydrogenolyzed withhydrogen in the presence of Raney nickel to furnish2-cyclobutylnaphthalene.

2-Cyclopentylnaphthalene can be prepared by heating naphthalene withcyclopentyl benzene sulfonate. 2-Cyclohexylnaphthalene can be similarlyprepared by employing cyclohexyl benzene sulfonate.

2-Acetylnaphthalene is prepared by treating2-(α-bromoethyl)-naphthalene, prepared as described above, with sodiumacetate in acetic acid to afford 2-(α-ethanoyloxyethyl)-naphthalenewhich upon base hydrolysis furnishes the 2-(α-hydroxyethyl)-naphthalene.The latter is oxidized with an equivalent of chromium trioxide inglacial acetic acid or 8N sulfuric acid to furnish 2-acetylnaphthalene.

2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treatingthe latter with aqueous sodium hypochlorite. The 2-carboxy group isesterified by conventional means, described herein, to furnish2-alkoxycarbonylnaphthalenes. By treating the latter with one equivalentof an alkali metal hydroxide, treating the resulting product withdiborane in an ether, such as diglyme, (dimethoxydiethyleneglycol),2-hydroxymethylnaphthalene is prepared.

The 2-hydroxymethyl group is esterified and etherified by conventionalmeans employed to esterify and etherify primary hydroxy groups.

2-Formylnaphthalene is prepared from 2-hydroxymethylnaphthalene bytreating the latter with manganese dioxide in a halo hydrocarbonsolvent.

2-Cyanonaphthalenes are prepared by refluxing 2-formylnaphthalene withhydroxylamine hydrochloride and sodium acetate in ethanol to furnish thecorresponding oxime which is refluxed with acetic anhydride in thepresence of an acid catalyst to furnish 2-cyanonaphthalene.

Alternatively, the above substituents can be introduced on anaphthylacetic acid ester derivative by using an ethyl or vinylsubstituted naphthylacetic acid ester derivative as a starting material.

In the preferred embodiment of the present invention, the startingmaterials are not substituted with trifluoromethyl, difluoromethoxy,difluoromethylthio, methylmethylenedioxy, alkoxymethylthio,alkylthiomethyloxy, alkylthiomethylthio, tetrahydropyran-2'-yloxy,tetrahydrofuran-2'-yloxy, or 4'-alkoxytetrahydropyran-4'-yloxy groups,but rather, such groups are introduced on the 2-naphthalene acetic acidderivative via one of the final steps.

Another method of preparing the present compounds employs unsubstitutedand substituted 1-tetralones and can be illustrated by the followingreaction sequence: ##STR5## wherein alkyl and R¹⁸ are defined as above.

The 1-tetralones, the compounds of formula C, are heated with two ormore equivalents of a dialkyl carbonate, such as diethyl carbonate, inthe presence of one or more equivalents of an alkali metal hydride, suchas sodium hydride, potassium hydride, and the like, in a hydrocarbonsolvent, such as hexane, cyclohexane, heptane, isooctane, benzene,toluene, xylene, and the like, to afford the corresponding alkoxycarbonyl compounds of formula D. The latter are treated with an alkalimetal hydride in a hydrocarbon solvent; then the resulting products aretreated with an α-haloacetic acid ester, such as ethyl α-bromoacetate,methyl α-iodoacetate, and the like, to furnish the corresponding2-alkoxycarbonyl-2-(alkoxycarbonylmethyl)-1-tetralones, the compounds offormula E. The latter is hydrolyzed with an acid, such as hydrochloricacid, sulfuric acid, p-toluenesulfonic acid, and the like, to obtain the2-(carboxymethyl) compounds of formula F. The latter is reduced with areducing agent, such as sodium borohydride, lithium borohydride; or withone equivalent of hydrogen in the presence of Adam's catalyst, and thelike, to afford the hydroxy compounds of formula G which arehydrogenolyzed by treatment with an equivalent amount of hydrogen in thepresence of a hydrogenation catalyst, such as platinum, palladium, andthe like, to furnish the corresponding1,2,3,4-tetrahydro-2-naphthylacetic acid derivatives, the compounds offormula H. The compounds of formula H are esterified by conventionalmeans, such as the means described above, to afford the compounds offormula I, which are dehydrogenated by heating with palladium charcoalcatalyst at temperatures of 180° C and higher to furnish thecorresponding 2-naphthylacetic acid ester derivatives, the compounds offormula J. The latter compounds are hydrolyzed to the corresponding2-naphthylacetic acid derivatives, the compounds of formula K, byconventional hydrolysis, such as by treatment with an aqueous methanolic5% sodium hydroxide solution.

Disubstituted tetralones of formula L are also employed in the aboveprocess to prepare the corresponding disubstituted 2-naphthylacetic acidderivatives of formula M: ##STR6## wherein R⁸ is as defined above andR^(9') represents the same substituents as R⁹, but only at position 4, 7or 8.

By treating the compounds of formula D with an alkali metal hydride andthen with an α-halocarboxylic acid ester, such as methylα-bromopropionate and the like, the corresponding2-alkoxycarbonyl-2-(α-alkoxycarbonylalkyl)-1-tetralones are obtained.These compounds can be hydrolyzed, reduced, hydrogenolyzed, esterified,dehydrogenated and hydrolyzed by the means used to similarly treatcompounds of formula E, to obtain the corresponding 2-naphthyl-α-alkylacetic acid derivatives.

The 1-tetralones of formulas C and L are prepared by conventionaltechniques, for example, such as the process used to make6,7-dimethoxy-1-tetralone described above.

Alternatively, the 1-tetralones of formulas C and L can be prepareddirectly from naphthalenes by conventional means known to the art. Forexample, the substituted 1-tetralones can be prepared from substitutednaphthalenes. The substituted naphthalenes are reduced with two molarequivalents of hydrogen in the presence of a platinum, palladium, nickelcatalyst, or the like, to afford the corresponding substituted tetralin(hydrogenation of the unsubstituted ring is favored; when both rings aresubstituted, two products are obtained with different ring saturation).The substituted tetralin is then oxidized, such as with chromiumtrioxide in glacial acetic acid of 8N sulfuric acid, to obtain thesubstituted 1-tetralone.

The 1-tetralones substituted at positions 6 and 8 of formulas C and Lcan also be prepared from the corresponding 4-tetralones (which areintermediates in the above described preparation of naphthalenessubstituted at positions 6 and 8) by reducing and hydrogenolyzing thelatter with sodium borohydride and hydrogen in the presence of palladiumrespectively to afford the corresponding tetralins. The tetralins arethen oxidized with chromium trioxide in acetic acid to afford thecorresponding 1- and 4-tetralones substituted at positions 6 and 8. Thetetralones are separated by conventional means, such as fractionalcrystallization or distillation.

1-Substituted and 1,6-disubstituted 2-naphthylacetic acid derivativesalso can be prepared from 1-oxo-3,4-dihydro-2- 2H!naphthylacetic acidderivatives or 1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acidderivatives, the compounds of formula F or G respectively.

For example, the 1-chloro-2-naphthylacetic acid derivatives are preparedby first esterifying compounds of formula F by conventional means, suchas described above, and then chlorinating the resulting 1-oxo esters bya conventional technique, such as by treatment with phosphorouspentachloride, to furnish the corresponding 1-chloro-3,4-dihydrocompounds. The resulting 1-chloro products are then dehydrogenated byconventional means, preferably by refluxing in a hydrocarbon solventwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to furnish thecorresponding 1-chloro-2-naphthylacetic acid derivatives.

The 1-fluoro-2-naphthylacetic acid ester derivatives are prepared byesterifying the carboxy group of the corresponding1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid derivatives, thecompounds of formula G, and then treating the resulting ester with twoor more equivalents of 1-diethylamino-1,2,2-tri-fluoro-2-chloroethane ina halogenated hydrocarbon solvent to afford the corresponding 1-fluoroderivative. The latter upon treatment with DDQ, as described above,affords the corresponding 1-fluoro-2-naphthylacetic acid esterderivative.

By treating the 1-oxo-3,4-dihydro-2- 2H!naphthylacetic acid esterderivatives with an alkyl magnesium bromide, such as methyl magnesiumbromide, in a non-aqueous ether, such as diethylether, diisopropylether,dioxane, tetrahydrofuran, and the like, hydrolyzing the resultingproducts under acidic conditions, and then dehydrogenating the resulting1-alkyl-1,2,3,4-tetrahydro-2-naphthylacetic acid ester derivatives byconventional techniques, such as the techniques described above, thecorresponding 1-alkyl-2-naphthylacetic acid derivatives are obtained.

1-Alkoxy-2-naphthylacetic acid ester derivatives are prepared bytreating 1-oxo-3,4-dihydro-2- 2H!naphthylacetic acid ester derivativeswith an alkylorthoformate, such as methylorthoformate, in the presenceof an acid catalyst, such as the ones described above, in a hydrocarbonsolvent and then dehydrogenating the resulting1-alkoxy-3,4-dihydro-2-naphthylacetic acid derivatives by conventionalmeans, such as described above.

1-Alkylthio-2-naphthylacetic acid ester derivatives can be prepared byhydrolyzing a 1-alkoxy-2-naphthylacetic acid ester derivative to obtainthe corresponding 1-hydroxy derivatives and then treating the latterwith an alkylmercaptan, such as methylmercaptan, ethylmercaptan, and thelike, in an acid environment at about 180° C under pressure greater thanatmospheric pressure for 3 hours or more.

The 1-substituted-2-naphthylacetic acid ester derivatives are hydrolyzedby conventional methods, such as by the means described above, to thefree acids.

Another method for the preparation of 4-substituted 2-naphthylaceticacid derivatives involves the treatment of benzene with an equivalent ofa 3-halocarbonyl dialkyl glutarate, such as dimethyl 3-chlorocarbonylglutarate and two or more equivalents of aluminum chloride in ahydrocarbon solvent to afford the corresponding dialkyl benzoylglutarate, which is reduced and hydrogenolyzed as the oxo-containingcompounds above to afford the corresponding dialkyl 3-benzyl glutarate.The latter is hydrolyzed by conventional means and the resulting3-benzyl glutaric acid is treated with concentrated sulfuric acid toafford the corresponding 1,2-dihydro-4-oxo-2- 3H!naphthylacetic acidderivative. The latter is reduced, halogenated, alkylated, esterifiedand dehydrogenated by the processes used to reduce, halogenate,alkylate, esterify and dehydrogenate the 1-oxo-3,4-dihydro-2-2H!naphthylacetic acid derivatives described above, to obtain 4-chloro-,4-fluoro-, 4-hydroxy-, 4-alkyl-, 4-alkoxy-, and4-alkylthio-2-naphthylacetic acid derivatives. The4-substituted-6-substituted-2-naphthylacetic acid derivatives areobtained by employing a monosubstituted benzene, such as methoxybenzene,in the above process.

Another method of preparing the 8-substituted 2-naphthylacetic acidderivatives involves treating an ester of phenylacetic acid with two ormore equivalents of succinic anhydride and aluminum chloride in anitrobenzene or carbon disulfide to afford the corresponding alkylp-(3-carboxy-1-oxopropyl)phenylacetate derivative, which is reduced andhydrogenolyzed by treatment with an alkali borohydride and palladiumcharcoal catalyst, respectively, to afford the ester ofp-(3-carboxypropyl)phenylacetic acid. The corresponding acid halide isprepared by treating the latter with a conventional halogenating agent,such as phosphorus tri- or pentabromide or -chloride or thionylchloride. The resulting ester of p-(3-halocarbonylpropyl)phenylaceticacid is treated with three or more equivalents of aluminum chloride in ahydrocarbon solvent to furnish the ester of 8-oxo-5,6-dihydro-2-7H!naphthylacetic acid. This compound can be reduced, halogenated,alkylated, esterified and dehydrogenated by the processes describedabove to obtain the 8-chloro-, 8-fluoro-, 8-hydroxy-, 8-alkyl-,8-alkoxy- and 8-alkylthio-2-naphthylacetic acid derivatives.

Another method by which the present compounds can be prepared involvesthe reaction of 2-tetralones with one or more equivalents of a1-alkoxycarbonylalkylidene triphenyl phosphorane, such as1-methoxycarbonylethylidene triphenyl phosphorane, to furnish thecorresponding 2,2-(1-alkoxycarbonylalkylidene)-tetralin. The latter uponheating with palladium charcoal catalyst affords the corresponding2-naphthylacetic acid ester derivative.

For this purpose, the 1-alkoxycarbonylalkylidene triphenyl phosphoranereactant is conveniently provided upon reaction of triphenylphosphinewith a 2-halocarboxylic acid ester in an organic reaction mediumfollowed by reaction with a base.

Thus, for example, by reacting 6-methoxy-2-tetralone with thetriphenylphosphorane derived from ethyl 2-halopropionate,2,2-(1'-carbethoxyeth-1', 1'-ylidene)-6-methoxytetralin is prepared.Dehydrogenation thereof provides ethyl 6-methoxynaphthyl-α-methylacetatewhich upon hydrolysis affords 6-methoxynaphthyl-α-methylacetic acid.

Unsubstituted and substituted 2-tetralones of the following formulas canbe utilized in the above process: ##STR7## wherein R⁸, R^(9') and R¹⁸are as defined above.

The substituted 2-tetralones of formulas N and O are prepared bytreating the corresponding 1-tetralones with butylnitrite in ether andthen esterifying the resulting 2-oximino-1-tetralones with an acidanhydride, such as acetic anhydride, in an organic acid, such as aceticacid, to obtain the substituted 2-acetylimino-2-tetralones. Theacetylimino substitutents are reduced to acetylamino substituents withhydrogen in the presence of palladium and the like. The keto groups arethen reduced to hydroxy groups with sodium borohydride or the like. Thesubstituted 2-acetylamino-1-hydroxytetralins are then treated withglacial acetic acid in the presence of concentrated acid to obtain thecorresponding substituted 2-tetralones of formulas N and O.

The 3,4-dihydro-2-naphthylacetic acid derivatives of formulas VI, VIIand VIII are prepared from the corresponding 2-naphthylacetic acidderivatives or the esters thereof by refluxing the latter in an alkanolwith two or more equivalents of an alkali metal, such as lithium,potassium, sodium, and the like. Preferably the 2-naphthylacetic acidderivative starting material is not substituted with hydroxy orconventional hydrolyzable ester, but rather, these groups are introducedlater by the means described herein.

The addition of an alkyl substituent at the α-position (with respect tothe acetic acid chain) to obtain the 2-naphthyl-α-alkylacetic acidderivatives is optional, but when the addition is required, it iscarried out following the preparation of the 2-naphthylacetic acidderivatives or the 3,4-dehydro derivatives thereof prepared as describedabove. The introduction of the α-alkyl substituents can be illustratedby the following reaction sequence: ##STR8## wherein R^(18') is alkyl,cycloalkyl, trifluoromethyl, vinyl, alkoxymethyl, fluoro, chloro,conventional hydrolyzable ester, oxyether, thioether, formyl,alkoxycarbonyl, acetyl, cyano or aryl;

Z is a carbon-carbon single bond or a carbon-carbon double bond;provided that when Z is a carbon-carbon double bond, R^(18') is alkyl,cycloalkyl, trifluoromethyl, fluoro, chloro, oxyether, thioether oraryl.

The 2-naphthylacetic acid derivatives, the compounds of formula P, areesterified by conventional means, such as being allowed to react with analkanol in the presence of boron trifluoride, to afford thecorresponding esters, the compounds of formula Q. The compounds offormula Q are treated with an alkali metal hydride such as sodiumhydride, potassium hydride, and the like, in an ether solvent, such asmonoglyme, and then with an alkyl halide, such as methyl iodide, toafford the corresponding 2-naphthyl-α-alkylacetic acid esterderivatives, the compounds of formula R. The latter are hydrolyzed byrefluxing in a basic solution to obtain the corresponding2-naphthyl-α-alkylacetic acid derivatives.

The ethynyl 2-naphthyl-α-alkylacetic acid derivatives are prepared fromvinyl 2-naphthyl-α-alkylacetic acid derivatives by brominating anddebrominating the latter's vinyl group by the means described above.Oxyether or alkoxymethyl 2-naphthyl-α-alkylacetic acid derivatives arehydrolyzed to obtain the hydroxy or hydroxymethyl derivativesrespectively. Alkoxycarbonyl 2-naphthyl-α-alkylacetic acid derivativesare hydrolyzed to obtain the carboxy derivatives.

2-Naphthylacetic acid derivatives substituted at other positions arealso employed in the above process.

The α-alkyl substituents are similarly introduced into other2-naphthylacetic acid derivatives substituted at positions 1, 4, 7, 8and/or 6. Prior to the above process, hydroxy groups are etherified andcarboxy groups are esterified to protect them from attack by reagentsused in subsequent elaborations. Such protected groups can beregenerated by hydrolysis after the process.

The introduction of other substituents on the α-carbon atom of theacetic acid moiety is also optional, but when carried out, is preferablydone after the preparation of the 2-naphthylacetic acid derivatives andthe esters thereof (including the 3,4-dihydro derivatives).

The α-difluoromethyl group can be introduced by treating the2-naphthylacetic acid ester derivatives with an alkali metal or alkalimetal hydride in a dialkyl carbonate, such as diethyl carbonate, toafford the corresponding α-alkoxycarbonyl derivatives. The latter istreated with chlorodifluoromethane and an alkali metal alkoxide, such aspotassium t-butoxide, in an ether solvent, preferably1,2-dimethoxyethane to afford the correspondingα-alkoxycarbonyl-α-difluoromethyl derivatives, which are hydrolyzed tofurnish the corresponding 2-naphthyl-α-carboxy-α-difluoromethylaceticacid derivatives. The deesterified product is decarboxylated by heatingto between 30° C and 150° C, until the evolution of carbon dioxideceases to give the corresponding 2-naphthyl-α-difluoromethylacetic acidderivatives.

By treating the above 2-naphthyl-α-alkoxycarbonylacetic acid esterderivatives with an equivalent of an alkali metal hydride in ahydrocarbon solvent, then with an alkyl halide, the corresponding2-naphthyl-α-alkoxycarbonyl-α-alkylacetic acid ester derivatives areobtained. The latter are hydrolyzed and decarboxylated to furnish thecorresponding 2-naphthyl-α-alkylacetic acid derivatives. This is analternative method of introducing the α-alkyl substituent.

The α-fluoro group is introduced by treating the 2-naphthylacetic acidester derivatives with two or more equivalents of an alkyl formate, suchas ethylformate, and three or more equivalents of an alkali metal oralkali metal hydride in a hydrocarbon solvent to afford thecorresponding α- hydroxymethylene derivatives which are treated with anequivalent of an alkali metal hydride and one equivalent of perchlorylfluoride to afford the corresponding α-fluoro-α-formyl derivatives. Thelatter are oxidized by conventional means, such as with chromiumtrioxide in glacial acetic acid or 8N sulfuric acid, to furnish thecorresponding α-fluoro-α-carboxy derivatives which are decarboxylated byheating to temperatures of 100° C or more to afford the corresponding2-naphthyl-α-fluoroacetic acid ester derivatives. The correspondingα-chloro derivatives are prepared by utilizing chlorine in place ofperchloryl fluoride in the above process.

The α, α-difluoromethylene group can be introduced by refluxing2-naphthyl-α-chloroacetic acid ester derivatives with an alkali metalhydroxide in an alkanol to afford the corresponding2-naphthyl-α-hydroxyacetic acid derivative. The carboxy groups of thelatter are re-esterified by conventional methods and the resultingesters are then oxidized by conventional means, such as described above,to obtain the corresponding α-oxo derivatives, which upon being refluxedwith one equivalent of difluoromethylidene triphenylphosphorane in ahydrocarbon solvent, affords the corresponding 2-naphthyl-α,α-difluoromethyleneacetic acid ester derivatives. The corresponding α,α-fluorochloromethylene derivatives are prepared by usingchlorofluoromethylidene triphenylphosphorane in place ofdifluoromethylidene triphenylphosphorane in the above process. Thedifluoromethylidene triphenylphosphorane is prepared by refluxing sodiumchlorodifluoroacetate with triphenylphosphine in dimethylformamide.Similarly, triphenyl chlorofluoromethylidene phosphorane is prepared byemploying sodium dichlorofluoroacetate.

The α, α-chloromethylene group can be introduced by treating2-naphthyl-α, α-hydroxymethyleneacetic acid ester derivatives withphosphorus pentachloride in a hydrocarbon solvent.

The α, α-fluoromethylene group can be introduced bytosylating-2-naphthyl-α, α-hydroxymethyleneacetic acid ester derivativeswith p-toluenesulfonyl chloride in a hydrocarbon solvent and thentreating the resulting tosylate with an alkali metal fluoride, such assodium fluoride. By utilizing an alkali metal chloride in the aboveprocess, the corresponding α, α-chloromethylene derivatives arefurnished.

The α, α-methylene group is introduced by treating the 2-naphthyl aceticacid ester derivatives with formaldehyde or paraformaldehyde and analkali metal alkoxide, such as sodium methoxide in dimethylsulfoxide.

The α, α-ethylene group is introduced by refluxing the 2-naphthyl-α,α-methyleneacetic acid ester derivatives with diiodomethane in thepresence of zinc-copper couple in an ether solvent.

In the preferred embodiment of this invention the hydroxy,hydroxymethyl, conventional hydrolyzable ester, alkoxymethyloxy,alkylthiomethyloxy, tetrahydrofuran-2'-yloxy, tetrahydropyran-2'-yloxy,4'-alkoxytetrahydropyran-4'-yloxy, alkoxymethylthio andalkylthiomethylthio are introduced after the introduction ofsubstitutents at the α-position of the 2-naphthyl acetic acidderivatives.

Those compounds containing a trifluoromethyl group are preferablyprepared from the corresponding methyl substituted 2-naphthylacetic acidester derivatives by treating the latter with chlorine and phosphorustrichloride in the presence of light to afford the correspondingtrichloromethyl derivatives, which, when refluxed with antimonytrifluoride in a hydrocarbon solvent, furnish the correspondingtrifluoromethyl substituted 2-naphthylacetic acid ester derivatives. Inthe preferred embodiment of the present invention the trifluoromethylgroup is introduced on the 2-naphthylacetic acid derivatives startingmaterial prior to the preparation of the corresponding 3,4-dihydroderivatives by the above described processes.

Those compounds containing difluoromethoxy groups are preferablyprepared from the corresponding alkoxy substituted 2-naphthylacetic acidester derivatives by refluxing the latter with 48% hydrobromic acid inacetic acid to furnish the free hydroxy derivatives which, upontreatment with chlorodifluoromethane and an alkali metal hydroxide inaqueous dioxane or tetrahydrofuran, affords the correspondingdifluoromethoxy substituted 2-naphthylacetic acid ester derivatives.

By utilizing alkylthio 2-naphthylacetic acid ester derivatives in theabove process, the corresponding difluoromethylthio derivatives areobtained.

The hydroxy groups are etherified by conventional methods, for example,by treatment with an alkali metal hydride and then with an alkylhalide,preferably an alkylbromide or iodide; or by treatment with a diazoalkaneor an alkanol in the presence of borontrifluoride in an ether solvent,and the like.

The alkoxymethyloxy groups are introduced by treating the hydroxysubstituted 2-naphthylacetic acid derivatives with analkoxychloromethane in dimethylformamide to afford the correspondingalkoxymethyloxy substituted 2-naphthylacetic acid derivatives. Thealkylthiomethyloxy substituted 2-naphthylacetic acid derivatives areprepared by utilizing an alkylthiochloromethane in the above process.

The alkoxymethylthio substituted 2-naphthylacetic acid derivatives areprepared by refluxing thio substituted 2-naphthylacetic acid derivativeswith an alkoxychloromethane in dimethylformamide. Thealkylthiomethylthio substituted derivatives are prepared by using analkylthiochloromethane in place of alkoxychloromethane in the aboveprocess.

The compounds containing tetrahydrofuran-2'-yloxy,tetrahydropyran-2'-yloxy, or 4'-alkoxytetrahydropyran-4'-yloxy groupsare preferably prepared from the corresponding hydroxy 2-naphthylaceticacid ester derivative by treatment with dihydrofuran, dihydropyran, or4'-alkoxy dihydropyran, such as 4'-methoxy dihydropyran, in the presenceof an acid catalyst.

The 4-alkoxy-2,6-dihydropyrans are prepared by treating4-oxotetrahydropyran with an alkanol in the presence of an acidcatalyst, and then pyrolyzing the resulting 4,4-dialkoxy tetrahydropyranin the presence of acid to afford the corresponding4-alkoxy-2,6-dihydropyran.

The compounds containing hydroxy ester groups are prepared from thehydroxy derivatives by conventional esterification means, such as byheating with an acid anhydride.

The foregoing general procedures are useful for the preparation of theother naphthylacetic acid derivatives hereof.

Upon their preparation, the naphthylacetic acid derivatives can beconverted to the corresponding amides, esters, and acid addition saltsthereof via methods known per se as described above.

The following examples illustrate the manner by which this invention canbe practiced and are not intended as limitations upon the overall scopehereof, but rather as illustrations of the present invention.

PREPARATION 1 Part A

A mixture of 12.2 g. of o-methoxy toluene, 20 g. of succinic anhydride,27 g. of aluminum chloride, and 250 ml. of carbon disulfide is stirredfor four hours; the mixture is poured into 500 g. of ice, and theproducts are isolated by extraction with benzene. The product, a mixtureof 2-methoxy-4-(3'-carboxy-1'-oxopropyl)-toluene and2-methoxy-5-(3'-carboxy-1'-oxopropyl)-toluene is reduced with sodiumborohydride, hydrogenolyzed with hydrogen in the presence of palladiumcharcoal catalyst, cyclized by treatment with concentrated sulfuric acidaccording to the procedures described in Part A of Example 3 to affordthe mixed product 6-methyl-7-methoxy-1-tetralone and7-methyl-6-methoxy-1-tetralone. The products are separated bydistillation and identified by nuclear magnetic resonance.

Part B

Ten grams of the above mixed products are hydrogenolyzed by treatmentwith 6 g. of sodium borohydride in ethanol at 25° C for six hours. Themixture is acidified with aqueous 1N hydrochloric acid and the products6-methyl-7-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalene and6-methoxy-7-methyl-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalene areisolated by benzene extraction. The products are hydrogenolyzed anddehydrogenated according to the procedures described in Part B ofExample 3 to give 2-methyl-3-methoxynaphthalene.

Similarly, 6-chloro-8-ethoxy-4-tetralone are prepared from1-chloro-3-ethoxybenzene. By means of the process described in Part B,6-chloro-8-ethoxynaphthalene and 6-ethoxy-8-chloronaphthalene areprepared from the corresponding 1-tetralones. The products are separatedby distillation and identified by nuclear magnetic resonance.

Part C

A mixture of 21 g. of 6-chloro-8-ethoxy tetralin (prepared from6-chloro-8-ethoxy-4-tetralone by reducing and hydrogenolyzing the latterby the means described in Part B above), 30 g. of chromium trioxide and500 ml. of glacial acetic acid is stirred for 24 hours at roomtemperature. The mixture is diluted with 500 ml. of aqueous ice-cold 10%sodium bisulfite, neutralized by the addition of aqueous 15% sodiumhydroxide, and extracted with methylene chloride. The extracts arecombined, washed with water, dried and evaporated to yield a mixture of6-chloro-8-ethoxy-1-tetralone and 6-chloro-8-ethoxy-4-tetralone. Theproducts are separated by distillation under reduced pressure.

Likewise, by means of the above process, 7-fluoro-1-tetralone isprepared from fluorobenzene, and β-fluoronaphthalene is prepared from7-fluoro-1-tetralone by means of the process described in Part B.

Similarly, 7-methoxy-1-tetralone, 7-isopropyl-1-tetralone,7-methylthio-1-tetralone, 6-chloro-7-methylthio-1-tetralone,6-fluoro-7-methyl--tetralone, 6-methoxy-7-fluoro-1-tetralone, 6,8-dimethyl-1-tetralone, 6-methylthio-8-cyclopropyl-1-tetralone,6-methyl-8-isopropyl-1-tetralone, 2-methylthio-3-chloronaphthalene,2-methyl-3-fluoronaphthalene, 2-fluoro-3-methoxynaphthalene,1,3-dimethylnaphthalene, 1-methylthio-3-cyclopropylnaphthalene, and1-isopropyl-3-methylnaphthalene are prepared from substituted benzenederivatives by means of the above processes.

PREPARATION 2 Part A

A mixture of 15.5 g. of 2-vinylnaphthalene, 23 g. of diiodomethane, 19.6g. of zinc-copper couple (comprising 19.5 g. of zinc and 0.1 g. ofcopper) and 500 ml. of diethyl ether is refluxed for eight hours; thecooled mixture is then filtered, washed with dilute hydrochloric acid,washed with water to neutrality, dried and evaporated to yield2-cyclopropylnaphthalene.

Part B

To a mixture of 23.1 g. of naphthyl magnesium bromide and 250 ml. ofdiethyl ether, 7 g. of cyclobutanone are slowly added. After theaddition, the mixture is refluxed for one hour, cooled, acidified withaqueous hydrochloric acid and filtered. The product is isolated bymethylene chloride extraction to furnish2-(1'-hydroxycyclobutyl)-naphthalene. The product is hydrogenated in 200ml. of ethanol with a molar equivalent of hydrogen in the presence of 50g. of Raney nickel; the reaction mixture is filtered after thehydrogenation and evaporated to furnish 2-cyclobutylnaphthalene.

Part C

To a mixture of 15.5 g. of 2-vinylnaphthalene and 300 ml. of chloroform,a 5% bromine chloroform solution is added at -10° C until the brominecolor persists. The mixture is then added to 200 ml. of ammoniacontaining 15 g. of sodium amide. The mixture is allowed to evaporate;the residue is extracted with diethyl ether. The extracts are combined,washed to neutrality with water, dried, and evaporated to yield2-ethynylnaphthalene.

PREPARATION 3

A mixture of 14.6 g. of 2-tetralone, 20 g. of p-fluorophenyl magnesiumbromide, and 200 ml. of diethyl ether is stirred for 4 hours and thenrefluxed for 1 hour. The mixture is acidified with the addition of 200ml. of 1N hydrochloric acid, filtered, and extracted with diethyl ether.The extracts are combined, washed with water to neutrality, filtered,dried and evaporated. The residue, containing2-p-fluorophenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5%palladium-on-charcoal catalyst; the resulting mixture is heated to 200°C for 6 hours, cooled, diluted with 250 ml. of chloroform, filtered, andevaporated to give 2-p-fluorophenylnaphthalene.

Similarly, 2-p-chlorophenylnaphthalene and 2-p-tolylnaphthalene areprepared by using p-chlorophenyl magnesium bromide and p-tolyl magnesiumbromide respectively in place of p-fluorophenyl magnesium bromide in theabove process.

EXAMPLE 1

To a mixture of 1.6 g. of β-methoxynaphthalene, 1.6 g. of acetylchloride, and 20 ml. of nitrobenzene, 4.0 g. of aluminum chloride areslowly added. The resulting mixture is stirred for 48 hours at 25° C;then it is washed with water until free of chloride. The mixture isdried over sodium sulfate and evaporated under reduced pressure. Theresidue, 2-acetyl-6-methoxynaphthalene, is refluxed in 2 ml. ofmorpholine containing one-half gram of sulfur for two hours; thereaction mixture is then filtered and evaporated. The resulting thioamide derivative is extracted with diethyl ether; the extracts arecombined and evaporated. The residue is refluxed in 10 ml. ofconcentrated hydrochloric acid for 2 hours, cooled to 25° C, and madealkaline with aqueous sodium hydroxide. The mixture is then extractedwith ether and the extracts discarded. The aqueous layer is acidifiedand the precipitated 6-methoxy-2-naphthylacetic acid filtered.

Similarly, 2-naphthylacetic acid, 6-chloro-2-naphthylacetic acid,6-fluoro-2-naphthylacetic acid, 6-ethoxy-2-naphthylacetic acid,6-ethylthio-2-naphthylacetic acid, 6-methylthio-2-naphthylacetic acid,6-methyl-2-naphthylacetic acid, 6-ethyl-2-naphthylacetic acid,6-isopropyl-2-naphthylacetic acid, 6-cyclopropyl-2-naphthylacetic acid,6-cyclohexyl-2-naphthylacetic acid, 6-hydroxy-2-naphthylacetic acid,6-vinyl-2-naphthylacetic acid, 6-ethynyl-2-naphthylacetic acid,6-formyl-2-naphthylacetic acid, 6-carboxy-2-naphthylacetic acid,6-methoxycarbonyl-2-naphthylacetic acid, 6-acetyl-2-naphthylacetic acid,6-cyano-2-naphthylacetic acid, 6-phenyl-2-naphthylacetic acid,6-p-chlorophenyl-2-naphthylacetic acid,6-methyl-8-fluoro-2-naphthylacetic acid,6-methyl-8-methoxy-2-naphthylacetic acid,6-chloro-8-methyl-2-naphthylacetic acid, 6,7-dichloro-2-naphthylaceticacid, 6-fluoro-7-methoxy-2-naphthylacetic acid,6-methoxy-7-fluoro-2-naphthylacetic acid, 6,7-dimethyl-2-naphthylaceticacid, 6,8-dimethoxy-2-naphthylacetic acid,6-methyl-8-fluoro-2-naphthylacetic acid,6-chloro-8-methyl-2-naphthylacetic acid,6-methyl-8-chloro-2-naphthylacetic acid are prepared from theirrespective corresponding naphthalene starting materials.

EXAMPLE 2 Part A

A mixture of 18 g. of 6-methoxy-1-tetralone, 60 g. of diethyl carbonate,2.5 g. of sodium hydride, and 200 ml. of toluene is heated to 60° C for5 hours. The mixture is cooled, acidified by the addition of 200 ml. of1N hydrochloric acid, and then extracted with three 75 ml. portions ofbenzene. The extracts are combined, washed with water to neutrality, anddried over sodium sulfate. The mixture, containing6-methoxy-2-ethoxycarbonyl-1-tetralone, is treated with 2.5 g. of sodiumhydride at room temperature with stirring. Twenty grams of ethylα-bromoacetate are then added and the mixture is allowed to stand for 12hours at room temperature. The mixture is added to 500 ml. of water andextracted with methylene chloride. The extracts are combined, washedwith water to neutrality, dried over sodium sulfate, and evaporated. Theresidue, containing6-methoxy-2-ethoxycarbonyl-2-(ethoxycarbonylmethyl)-1-tetralone, isrefluxed in 200 ml. of 6N hydrochloric acid for 24 hours and then thereflux mixture is evaporated. The residue, containing6-methoxy-2-(carboxymethyl)-1-tetralone, is reduced by treating it with200 ml. of ethanol containing 8 g. of sodium borohydride. After onehour, the mixture is acidified with the addition of 100 ml. of 3Nhydrochloric acid, and the resulting mixture is extracted with severalportions of methylene chloride. The extracts are combined, washed withwater to neutrality, dried over sodium sulfate, and evaporated. Theresidue, containing6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, ishydrogenolyzed by hydrogenating with one equivalent of hydrogen inacetic acid containing 300 mg. of 5% palladium-on-barium sulfate. Thehydrogenation mixture is filtered and evaporated. The residue,containing 6-methoxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, isdissolved in 200 ml. of diethyl ether and the mixture is then added to a100 ml. solution of diethyl ether containing 4 g. of diazomethane. Themixture is then evaporated to dryness. The esterified residue isdehydrogenated by adding it to 1 g. of 10% palladium-on-charcoal andheating the resulting mixture for 6 hours at 200° C. The cooled mixtureis diluted with 200 ml. of chloroform, filtered, and evaporated toafford methyl 6-methoxy-2-naphthylacetate.

Similarly, methyl 6-methyl-2-naphthylacetate,methyl-6-methylthio-2-naphthylacetate, and methyl6-chloro-2-naphthylacetate are prepared from 6-methyl-1-tetralone,6-methylthio-1-tetralone and 6-chloro-1-tetralone, respectively, bymeans of the above process.

By means of the above process, methyl 7-methyl-2-naphthylacetate, methyl7-ethyl-2-naphthylacetate, methyl 7-isopropyl-2-naphthylacetate, methyl7-fluoro-2-naphthylacetate, methyl 7-chloro-2-naphthylacetate, methyl7-methylthio-2-naphthylacetate, methyl 7-methoxy-2-naphthylacetate, andmethyl 7-propoxy-2-naphthylacetate are prepared from7-methyl-1-tetralone, 7-ethyl-1-tetralone, 7-isopropyl-1-tetralone,7-fluoro-1-tetralone, 7-chloro-1-tetralone, 7-methoxy-1-tetralone,7-methylthio-1-tetralone, and 7-hydroxy-1-tetralone, respectively.

Part B

A solution of 4.2 g. of diazomethane and 75 ml. of diethyl ether isadded to a mixture of 23.6 g. of6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid and 150 ml.of diethyl ether. The reaction mixture is stirred until colorless; thenit is evaporated. The residue, containing methyl6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate is esterifiedby treatment with 240 mg. of sodium hydride in 25 ml. of methanolfollowed by the addition of 2.4 g. of methyl iodide. The product, methyl1,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylacetate, is dehydrogenated byheating it with 2 g. of 10% palladium-on-charcoal catalyst; theresulting mixture is heated to 210° C for 12 hours. The cooled mixtureis then diluted with 150 ml. of methylene chloride, filtered, andevaporated to yield methyl 1,6-dimethoxy-2-naphthylacetate. The productis refluxed in a mixture of 150 ml. of glacial acetic acid and 150 ml.of 48% hydrobromic acid for ten minutes. The product is extracted withmethylene chloride. The extracts are combined, washed with water toneutrality, dried over sodium sulfate, filtered and evaporated to yielda mixture of methyl 1-hydroxy-6-methoxy-2-naphthylacetate and methyl1-methoxy-6-hydroxy-2-naphthylacetate. The compounds are separated bydistillation under reduced pressure and identified by nuclear magneticspectroscopy.

Similarly, methyl 1-hydroxy-2-naphthylacetate, methyl6-fluoro-1-hydroxy-2-naphthylacetate, methyl6-chloro-1-hydroxy-2-naphthylacetate, methyl6-methyl-1-hydroxy-2-naphthylacetate,methyl-6-cyclopropyl-1-hydroxy-2-naphthylacetate, methyl1,6-dihydroxy-2-naphthylacetate, methyl6-methylthio-1-hydroxy-2-naphthylacetate, and methyl6-ethyl-1-hydroxy-2-naphthylacetate are prepared from the correspondingunsubstituted and 6-substituted1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid by means of the aboveprocess.

Part C

To a mixture of 10 g. of boron trifluoride and 100 g. of methanol, 23 g.of 6-methoxy-2-(carboxymethyl)-1-tetralone are added. The reactionmixture is stirred for one hour and then evaporated to dryness. Theresidue, containing 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone,is converted to the enol ether by treating with a mixture of 11 g. oftrimethylorthoformate, 0.2 g. of p-toluenesulfonic acid and 200 ml. ofbenzene. The reaction mixture is allowed to stand for 24 hours; then itis washed with water to neutrality, dried over sodium sulfate, filtered,and evaporated. The residue, containing methyl1,6-dimethoxy-3,4-dihydro-2-naphthylacetate, is refluxed in a mixture of45 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 200 ml. of xylenefor six hours; the mixture is then filtered and evaporated to dryness.The residue is taken up in 200 ml. of acetone; this mixture ischromatographed on alumina and evaporated to yield methyl1,6-dimethoxy-2-naphthylacetate.

Similarly, methyl 1-methoxy-6-methyl-2-naphthylacetate, methyl1-methoxy-6-ethyl-2-naphthylacetate, methyl1-methoxy-6-fluoro-2-naphthylacetate, methyl1-methoxy-2-naphthylacetate, methyl1-methoxy-6-isopropyl-2-naphthylacetate, and methyl1-methoxy-6-methylthio-2-naphthylacetate are prepared from thecorresponding unsubstituted and 6-substituted2-(carboxymethylene)-1-tetralones by means of the above process.

By substituting other trialkyl orthoformates for trimethyl orthoformatein the above process, the corresponding1-alkoxy-6-substituted-2-naphthylacetic acid esters are prepared. Byemploying triethyl orthoformate in the above process, methyl1-ethoxy-6-methoxy-2-naphthylacetate is furnished.

Part D

To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethylether, 25 g. of 6-methoxy-2-(methoxycarbonyl-methylene)-1-tetralone areadded. The alkylating mixture is refluxed for one hour after it has beenallowed to stand for one hour; the mixture is made acidic to litmus bythe addition of 1N methanolic HCl, filtered, and evaporated. Theresidue, containing methyl1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of10% palladium-on-charcoal and the resulting mixture is heated to 180° Cfor 6 hours. The mixture is cooled, diluted with 200 ml. of chloroform,filtered, and evaporated to yield methyl1-methyl-6-methoxy-2-naphthylacetate.

Similarly, methyl 1-methyl-2-naphthylacetate, methyl1-methyl-6-chloro-2-naphthylacetate, methyl1-methyl-6-fluoro-2-naphthylacetate, methyl1,6-dimethyl-2-naphthylacetate, methyl1-methyl-6-methylthio-2-naphthylacetate, and methyl1-methyl-6-ethoxy-2-naphthylacetate are prepared from the correspondingunsubstituted and 6-substituted 2-methoxycarbonylmethyl-1-tetralones bymeans of the above process.

By employing ethyl magnesium bromide, isopropyl magnesium bromide, andhexyl magnesium bromide with 2-(methoxycarbonylmethyl)-1-tetralone inthe above process, the following are prepared: methyl1-ethyl-2-naphthylacetate, methyl 1-isopropyl-2-naphthylacetate, andmethyl 1-methyl-2-naphthylacetate.

Part E

To a mixture of 25 g. of 6-methoxy-2-(methoxycarbonylmethyl)-1-tetraloneand 150 ml. of benzene, 21 g. of phosphorus pentachloride are slowlyadded. After the addition, the chlorination mixture is allowed to standfor an additional five hours; then it is added to 500 g. of ice andextracted with xylene. The extracts, containing methyl1-chloro-6-methoxy-3,4-dihydro-2-naphthylacetate, are combined, washedwith water to neutrality and dried over sodium sulfate; then 23 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the resultingmixture is refluxed for five hours. The dehydrogenation mixture iscooled, filtered, and evaporated. The residue is taken up in acetone andchromatographed on alumina and evaporated to yield methyl in1-chloro-6-methoxy-2-naphthylacetate.

Similarly, methyl 1-chloro-2-naphthylacetate, methyl1-chloro-6-methyl-2-naphthylacetate, methyl1-chloro-6-isopropyl-2-naphthylacetate, methyl1-chloro-6-hydroxy-2-naphthylacetate, methyl1-chloro-6-fluoro-2-naphthylacetate, methyl1,6-dichloro-2-naphthylacetate, methyl1-chloro-6-ethylthio-2-naphthylacetate, and methyl1-chloro-6-methylthio-2-naphthylacetate are prepared from thecorresponding unsubstituted or 6-substituted2-(methoxycarbonylmethyl)-1-tetralone by means of the above process.

Part F

A mixture of 25 g. of methyl 1,6-dimethoxy-2-naphthylacetate, 50 g. of48% aqueous hydrobromic acid and 50 ml. of glacial acetic acid arerefluxed for two hours. The mixture is cooled, neutralized with thecautious addition of aqueous 5% sodium carbonate, and extracted withmethylene chloride. The extracts are combined, washed with water, driedover sodium sulfate, and evaporated to dryness. The residue, containingmethyl 1,6-dihydroxy-2-naphthylacetate is thioetherified by adding it toa mixture of 50 g. of methylmercaptan and 1 ml. of concentrated sulfuricacid; the mixture is heated to 180° C under pressure for 12 hours. Themixture is cooled, diluted with 150 ml. of benzene, washed with water toneutrality, dried over sodium sulfate, and evaporated. The residue isrefluxed in 200 ml. of methanol containing 10 g. of sodium methoxide forone hour; the product is extracted with methylene chloride. The extractsare combined, washed, dried and evaporated to give methyl1,6-dimethylthio-2-naphthylacetic acid.

Similarly, methyl 1-methylthio-2-napthylacetate, methyl1-methylthio-6-methyl-2-naphthylacetate, methyl1-methylthio-6-fluoro-2-naphthylacetate, and methyl1-methylthio-6-chloro-2-naphthylacetate are prepared from thecorresponding unsubstituted and 6-substituted methyl1-methoxy-2-naphthylacetates by means of the above process.

By utilizing ethylmercaptan, isopropylmercaptan or pentylmercaptan withmethyl 1-hydroxy-2-naphthylacetate in the above process, the followingare prepared: methyl 1-ethylthio-2-naphthylacetate, methyl1-isopropyl-2-naphthylacetate, or methyl 1-pentylthio-2-naphthylacetate.

By treating 25 g. of methyl 6-methoxy-1-hydroxy-2-naphthylacetate with10 ml. of methylmercaptan as described above for the 1,6-dihydroxycompound, methyl 6-methoxy-1-methylthio-2-naphthylacetate is obtained.

Part G

A mixture of 25 g. of methyl6-methoxy1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate, 38 g. of1-diethylamino-1,1,2trifluoro-2-chloroethane and 150 ml. of methylenechloride are allowed to stand for 24 hours. The fluorination reactionmixture is added to 250 ml. of water containing 12 g. of hydrogenchloride; the resulting mixture is separated and the methylene chloridephase is washed with water, dried over sodium sulfate, and evaporated toyield methyl 6-methoxy-1-fluoro-1,2,3,4-tetrahydro-2-naphthylacetate and6-methoxy-1,2-dihydro-2-naphthylacetate. The mixture is separated onalumina eluting with acetone: diethyl ether (1:4) and the separatedfractions are identified by ultraviolet spectroscopy. The fractioncontaining methyl 6-methoxy-1-fluoro-2-naphthylacetate is evaporated andthe residue is refluxed with 23 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml. of xylene for sixhours. The cooled mixture is filtered and chromatographed on aluminaeluting with chloroform. The fraction containing the product isevaporated to yield methyl 6-methoxy-1-fluoro- 2-naphthylacetate.

Similarly, methyl 1,6-difluoro-2-naphthylacetate, methyl1-fluoro-6-chloro-2-naphthylacetate, methyl1-fluoro-6-methyl-2-naphthylacetate, methyl1-fluoro-6-ethyl-2-naphthylacetate, methyl 1-fluoro-2-naphthylacetate,and methyl 1-fluoro-6-methylthio-2-naphthylacetate are prepared from thecorresponding unsubstituted and 6-substituted methyl1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetates.

Part H

A mixture of 25 g. of methyl 1,6-dimethoxy-2-naphthylacetate, 15 g. ofsodium carbonate, 200 ml. of methanol, and 25 ml. of water are allowedto stand for 24 hours. The reaction mixture is then acidified with 200ml. of 2N hydrochloric acid and extracted with methylene chloride. Theextracts are combined, washed with water, dried over sodium sulfate, andevaporated to yield 1,6-dimethoxy-2-naphthylacetic acid.

Likewise, the methyl 2-naphthylacetates prepared in the preceding partsare hydrolyzed to the corresponding 2-naphthylacetic acids.

EXAMPLE 3 Part A

To a mixture of 11 g. of chlorobenzene, 26 g. of aluminum chloride and250 ml. of carbon disulfide are added 22 g. of dimethyl 3-chlorocarbonylglutarate. The resulting mixture is poured into 500 ml. of ice waterafter it has been allowed to stand for 2 hours. The aqueous mixture isextracted with methylene chloride; the extracts are combined, washed toneutrality with water, dried over sodium sulfate, and evaporated to givedimethyl 3-(p-chlorobenzoyl)-glutarate. The latter compound is reducedand hydrogenolyzed by means of the procedures described in Part A ofExample 2 to furnish dimethyl 3-(p-chlorobenzyl)-glutarate. Theglutarate derivative and 200 ml. of concentrated hydrochloric acid isrefluxed for three hours, and then diluted with 500 ml. of water and theproduct extracted with ether. The residue, containing3-(p-chlorobenzyl)-glutaric acid, is taken up in 100 ml. of concentratedsulfuric acid and allowed to stand for 1 hour at room temperature; thereaction mixture is then diluted with a kilogram of ice and extractedwith methylene chloride. The extracts are combined, washed with water,dried over sodium sulfate, and evaporated to yield7-chloro-3-(carboxymethyl)-1-tetralone. The latter is esterified byadding it to a mixture of 10 g. of boron trifluoride etherate and 150ml. of methanol. The resulting mixture is evaporated after being allowedto stand for four hours to furnish7-chloro-3-(methoxycarbonylmethyl)-1-tetralone.

Similarly, 3-(methoxycarbonylmethyl)-1-tetralone,7-methyl-3-(methoxycarbonylmethyl)-1-tetralone,7-ethyl-3-(methoxycarbonylmethyl)-1-tetralone,7-cyclopropyl-3-(methoxycarbonylmethyl)-1-tetralone,7-isopropyl-3-(methoxycarbonylmethyl)-1-tetralone,7-methylthio-3-(methoxycarbonylmethyl)-1-tetralone,7-fluoro-3-(methoxycarbonylmethyl)-1-tetralone,7-methoxy-3-(methoxycarbonylmethyl)-1-tetralone,7-ethoxy-3-(methoxycarbonylmethyl)-1-tetralone, and7-ethylthio-3-(methoxycarbonylmethyl)-1-tetralone are prepared frombenzene, methylbenzene, ethylbenzene, cyclopropylbenzene,isopropylbenzene, methylthiobenzene, fluorobenzene, methoxybenzene,ethoxybenzene and methylthiobenzene, respectively, by means of the aboveprocess.

Part B

To a mixture of 8 g. of sodium borohydride and 150 ml. of methanol, 23.5g. of 7-fluoro-3-(methoxycarbonylmethyl)-1-tetralone are added. Themixture is diluted with 250 ml. of 2N hydrochloric acid after standingfor four hours at 25° C; the aqueous mixture is then extracted withchloroform. The extracts are combined, washed with water to neutrality,dried over sodium sulfate, filtered, and evaporated to yield methyl6-fluoro-4-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate. The lattercompound is dehydrogenated by the process described in Part B of Example2 to furnish methyl 6-fluoro-4-hydroxy-2-naphthylacetate.

Similarly, the 1-tetralones, prepared by means of the process of Part Aabove, are treated as described above to afford the corresponding4-hydroxy 2-naphthylacetic acid ester derivatives. Accordingly, methyl6-methyl-4-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate and methyl6-methyl-4-hydroxy-2-naphthylacetate are prepared from7-methyl-3-(methoxycarbonylmethyl)-1-tetralone by means of the abovedescribed processes.

Part C

7-Methoxy-3-(methoxycarbonylmethyl)-1-tetralone is converted to the enolether and dehydrogenated by means of the processes described in Part Cof Example 2 to furnish methyl 4,6-dimethoxy-2-naphthylacetate.

Similarly, other methyl 4-alkoxy-2-naphthylacetates are prepared fromthe corresponding unsubstituted- or7-substituted-3-(methoxycarbonylmethyl)-1-tetralones. Accordingly,methyl 4-methoxy-2-naphthylacetate is prepared from3-(methoxycarbonylmethyl-1-tetralone.

Part D

7-Methyl-3-(methoxycarbonylmethyl)-1-tetralone is alkylated anddehydrogenated by the processes described in Part D of Example 2 toafford methyl 4,6-dimethyl-2-naphthylacetate.

Similarly, other unsubstituted- or7-substituted-3-(methoxycarbonylmethyl)-1-tetralones are alkylated anddehydrogenated to furnish the corresponding unsubstituted- or6-substituted-methyl 4-alkyl-2-naphthylacetates. Thus, methyl4-isopropyl-6-chloro-2-naphthylacetate is prepared from7-chloro-3-(methoxycarbonylmethyl)-1-tetralone and isopropyl magnesiumbromide.

Part E

7-Chloro-3-(methoxycarbonylmethyl)-1-tetralone is chlorinated anddehydrogenated by the procedures described in Part E of Example 2 toafford methyl 4,6-dichloro-2-naphthylacetate.

Similarly, other unsubstituted or 6-substituted methyl4-chloro-2-naphthylacetates are prepared from the correspondingunsubstituted or 7-substituted 3-(methoxycarbonylmethyl)-1-tetralone bymeans of the aforementioned procedures. Accordingly, methyl4-chloro-6-methylthio-2-naphthylacetate is prepared from7-methylthio-3-(methoxycarbonylmethyl)-1-tetralone.

Part F

Methyl 6-methoxy-2-naphthylacetate is thioetherified by the proceduredescribed in Part F of Example 2 to afford methyl4-methylthio-6-methoxy-2-naphthylacetate.

Similarly, methyl 4-methylthio-2-naphthylacetate, methyl4-methylthio-6-methyl-2-naphthylacetate, methyl4-methylthio-6-chloro-2-naphthylacetate, methyl4-methylthio-6-fluoro-2-naphthylacetate, and methyl4,6-dimethylthio-2-naphthylacetate are prepared from the correspondingunsubstituted and 6-substituted methyl 4-hydroxy-2-naphthylacetates bymeans of the above processes.

Part G

Methyl 6-methyl-4-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate isfluorinated and dehydrogenated by means of the procedures described inPart G of Example 2 to afford methyl4-fluoro-6-methyl-2-naphthylacetate.

Similarly, other 4-hydroxy-1,2,3,4-tetrahydro compounds, prepared bymeans of the processes of Part B of this example, are fluorinated anddehydrogenated to afford the corresponding methyl4-fluoronaphthylacetate derivative. Thus, methyl6-methoxy-4-fluoro-2-naphthylacetate is prepared from methyl6-methoxy-4-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate.

Part H

Methyl 1,6-dimethoxy-2-naphthylacetate is hydrolyzed by the means of theprocess described in Part H of Example 2 to furnish1,6-dimethoxy-2-naphthylacetic acid.

Likewise, the other 2-naphthylacetic acid ester derivatives of thisexample are hydrolyzed to the corresponding 2-naphthylacetic acidderivatives.

EXAMPLE 4 Part A

To a mixture of 18 g. of methyl phenylacetate, 26 g. of aluminumchloride and 150 ml. of carbon disulfide, 20 g. of succinic anhydrideare added. The reaction mixture is allowed to stand for two hours at 35°C; then it is added to a liter of ice water and extracted with methylenechloride. The extracts are combined, washed, dried, and evaporated togive methyl p-(3'-carboxy-1'-oxopropyl)-phenylacetate. This derivativeis reduced with sodium borohydride and dehydroxylated with palladiumcharcoal catalyst by the procedures described in Part A of Example 2 toafford methyl p-(3'-carboxypropyl)-phenylacetate. This derivative isrefluxed in 50 ml. of thionyl chloride for three hours and then it isevaporated. The residue, containing methylp-(3'-chlorocarbonylpropyl)-phenylacetate, is taken up in 175 ml. ofbenzene containing 40 g. of aluminum chloride. The resulting mixture isstirred for 2 hours at 20° C; then it is added to a liter of ice andwater and extracted with methylene chloride. The extracts are combined,washed with water to neutrality, dried over sodium sulfate, andevaporated to give 7-(methoxycarbonylmethyl)-1-tetralone.

Part B

Methyl 8-hydroxy-2-naphthylacetate is prepared from7-(methoxycarbonylmethyl)-1-teralone by reducing the latter with anequivalent amount of sodium borohydride and dehydrogenating theresulting hydroxy derivative by heating with palladium charcoal catalystby the processes described in Part A of Example 2.

Part C

Methyl 8-methoxy-2-naphthylacetate is prepared from7-(methoxycarbonylmethyl)-1-tetralone by means of the esterification anddehydrogenation processes described in Part C of Example 2.

Part D

Methyl 8-methyl-2naphthylacetate is prepared from7-(methoxycarbonylmethyl)-1-tetralone by means of the alkylation anddehydrogenation procedure described in Part D of Example 2.

Similarly, methyl 8-ethyl-2-naphthylacetate and methyl8-isopropyl-2-naphthylacetate are prepared from7-(methoxycarbonylmethyl)-1-tetralone by utilizing ethyl magensiumbromide and isopropyl magnesium bromide, respectively, in the alkylationprocedure.

Part E

By means of the chlorination and dehydrogenation procedures described inPart A of Example 2, methyl 8-chloro-2-naphthylacetate is prepared from7-(methoxycarbonylmethyl)-1-tetralone.

Part F

Methyl 8-methylthio-2-naphthylacetate is prepared from methyl8-hydroxy-2-naphthylacetate by means of the thioesterification processdescribed in Part F of Example 2.

Part G

Methyl 8-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate (prepared from7-(methoxycarbonylmethyl)-1-tetralone by means of the reduction processdescribed in Part A of Example 2) is fluorinated and dehydrogenated bymeans of the processes described in Part G of Example 2 to afford methyl8-fluoro-2-naphthylacetate.

Part H

8-Methoxy-2-naphthylacetic acid is prepared from methyl8-methoxy-2-naphthylacetate by means of the hydrolysis proceduredescribed in Part H of Example 2.

Similarly, the other ester derivatives prepared by the above proceduresare hydrolyzed.

EXAMPLE 5

To a mixture of 22 g. of methyl 6-methyl-2-naphthylacetate, 2.5 g. ofsodium hydride and 150 ml. of 1,2-dimethoxyethane, 25 g. of methyliodideare added. The reaction mixture is allowed to stand for several hours;then it is diluted with ethanol followed by water and extracted withmethylene chloride. The extracts are combined, washed with water toneutrality, dried over sodium sulfate, filtered, and evaporated to yieldmethyl 6-methyl-2-naphthyl-α-methylacetate. This derivative ishydrolyzed by means of the process described in Part H of Example 2 toobtain 6-methyl-2-naphthyl-α-methylacetic acid.

6-Methyl-2-naphthyl-α-ethylacetic acid is prepared by using ethyliodidein place of methyliodide in the above process.

Similarly, 2-naphthyl-α-methylacetic acid,1-methyl-2-naphthyl-α-methylacetic acid,1-fluoro-2-naphthyl-α-methylacetic acid,1-methoxy-2-naphthyl-α-methylacetic acid,1,6-dimethylthio-2-naphthyl-α-methylacetic acid,4-ethyl-2-naphthyl-α-ethylacetic acid,4-chloro-2-naphthyl-α-methylacetic acid,4-methoxy-2-naphthyl-α-methylacetic acid,4-methyl-6-fluoro-2-naphthyl-α-methylacetic acid,4-fluoro-6-methoxy-2-naphthyl-α-methylacetic acid,6-ethoxy-2-naphthyl-α-methylacetic acid,6-ethyl-2-naphthyl-α-methylacetic acid,6-methoxymethyl-2-naphthyl-α-methylacetic acid,6-trifluoro-2-naphthyl-α-methylacetic acid,6-isopropyl-2-naphthyl-α-methylacetic acid,6-vinyl-2-naphthyl-α-methylacetic acid,6-cyclopropyl-2-naphthyl-α-methylacetic acid,6-fluoro-2-naphthyl-α-methylacetic acid,6-chloro-2-naphthyl-α-methylacetic acid,6-chloro-2-naphthyl-α-ethylacetic acid,6-acetyl-2-naphthyl-α-methylacetic acid,6-methoxy-2-naphthyl-α-methylacetic acid,6-methoxymethylene-2-naphthyl-α-methylacetic acid,6-methylthio-2-naphthyl-α-methylacetic acid,6-ethylthio-2-naphthyl-α-methylacetic acid,6-fluoro-7-methyl-2-naphthyl-α-methylacetic acid,6-methyl-7-methoxy-2-naphthyl-α-methylacetic acid, 6-methylthio-7-fluoro-2-naphthyl-α-methylacetic acid,7-chloro-2-naphthyl-α-methylacetic acid,7-methoxy-2-naphthyl-α-methylacetic acid,7-methyl-2-naphthyl-α-methylacetic acid,8-methyl-2-naphthyl-α-methylacetic acid,8-ethoxy-2-naphthyl-α-methylacetic acid,8-fluoro-2-naphthyl-α-methylacetic acid,8-isopropylthio-2-naphthyl-α-methylacetic acid,6,8-dimethyl-2-naphthyl-α-methylacetic acid, and6,8-dichloro-8-methyl-2-naphthyl-α-methylacetic acid are prepared fromthe corresponding methyl 2-naphthylacetate derivatives.

EXAMPLE 6

To a mixture of 25.2 g. of methyl 6-vinyl-2-naphthyl-α-methylacetate and300 ml. of chloroform, a 5% bromine chloroform solution is added at -10°C until the bromine color persists. The mixture is then added to 200 ml.of ammonia containing 15 g. of sodium amide. The mixture is allowed toevaporate; the residue is extracted with diethyl ether. The extracts arecombined, washed to neutrality with water, dried, and evaporated toyield methyl 6-ethynyl-2naphthyl-α-methylacetate.

Similarly, ethyl 6-ethynyl-2-naphthyl-α-difluoromethylacetate isprepared from ethyl 6-vinyl-2-naphthyl-60-difluoromethylacetate.

EXAMPLE 7

To a mixture of 23 g. of ethyl 6-methoxy-2-naphthylacetate, 7 g. ofsodium metal wire, and 150 ml. of benzene, 15 g. of ethyl formate areadded; the resulting mixture is stirred for 24 hours and then 100 ml. ofethanol are added. The reaction mixture is made acidic by the additionof 500 ml. of 1N hydrochloric acid and then extracted with benzene. Theextracts are combined, washed with water to neutrality, dried oversodium sulfate, and filtered. The benzene solution, which contains ethyl6-methoxy-2-naphthyl-α,α-hydroxymethylacetate, is treated with 2.4 g. ofsodium hydride; the resulting mixture is then treated with 3.6 g. ofchlorine and the reaction mixture is allowed to stand for two hours at25° C and then evaporated. The residue, containing ethyl6-methoxy-2-naphthyl-α-formyl-α-chloroacetate, is taken up in methylenechloride, washed with water to neutrality, dried, filtered, andevaporated. The residue is taken up in 95% acetic acid containing 20 g.of chromium trioxide and the resulting mixture allowed to stand for twohours; the mixture is then diluted with water and extracted withmethylene chloride. The extracts are combined, washed to neutrality,dried, filtered, and evaporated. The residue, containing ethyl6-methoxy-2-naphthyl-α-carboxy-α-chloroacetate, is heated to 50° C toafford ethyl 6-methoxy-2-naphthyl-α-chloroacetate.

By using 9.3 g. of perchloryl fluoride in place of chlorine in the aboveprocess, ethyl 6-methoxy-2-naphthyl-α-fluoroacetate is afforded.

Similarly, other 2-naphthylacetic acid ester derivatives are chlorinatedor fluorinated in the α-position. Thus, methyl2-naphthyl-α-chloroacetate and methyl 2-naphthyl-α-fluoroacetate areprepared from methyl 2-naphthylacetate by means of the above processes.

EXAMPLE 8

To a mixture of 30 g. of methyl6,7-dichloro-2-naphthyl-α,α-hydroxymethyleneacetate (prepared via theprocedure described in Example 6) and 150 ml. of benzene, 20 g. ofphosphorus pentachloride are slowly added. The reaction mixture isstirred for 4 hours after the completion of the addition; then 100 ml.of pyridine are added followed by the addition of 500 ml. of water. Thereaction mixture is filtered; the product is isolated from the filtrateby extraction with methylene chloride to yield methyl6,7-dichloro-2naphthyl-α,α-chloromethyleneacetate.

Similarly, methyl 6methylthio-2-naphthyl-α,α-chloromethyleneacetate isprepared from methyl6-methylthio-2-naphthyl-α,α-hydroxymethyleneacetate.

EXAMPLE 9

A mixture of 25 g. of methyl 6-methyl-2naphthyl-α-chloroacetate, 10 g.of sodium hydroxide, and 200 ml. of ethanol is refluxed for 2 hours. Thecooled mixture is acidified by the addition of 1N hydrochloric acid. Theresulting product, methyl 6-methyl-2naphthyl-α-hydroxyacetate, isisolated by extractions with methylene chloride. The product is oxidizedby means of the oxidation procedure described in Example 6 to givemethyl 6-methyl-2-naphthyl-α-oxoacetate. The latter product is refluxedwith 31 g. of difluoromethylene triphenyl phosphorane (prepared byallowing sodium chlorodifluoroacetate to react with triphenyl phosphinein diethyl ether) in 150 ml. of benzene. The resulting mixture isdistilled under vacuum. The distillate is evaporated to yield methyl2-naphthyl-α,α-difluoromethyleneacetate.

Methyl 6-methyl-α,α-chlorofluoromethyleneacetate is prepared by using 33g. of chlorofluoromethylene triphenyl phosphorane (prepared by allowingsodium dichlorofluoroacetate to react with triphenyl phosphine) in placeof difluoromethylene triphenyl phosphorane.

Similarly, other 2-naphthyl-α,α-difluoromethyleneacetic acid esterderivatives and 2-naphthyl-α,α-chlorofluoromethyleneacetic acid esterderivatives are prepared from the corresponding2-naphthyl-α-chloroacetate derivatives by means of the above describedprocedures. Accordingly, methyl6-fluoro-7-methoxy-2naphthyl-α,α-difluoromethyleneacetate and methyl6-fluoro-7-methoxy-2-naphthyl-α,α-chlorofluoromethyleneacetate areprepared from methyl 6-fluoro-7-methoxy-2-naphthyl-α-chloroacetate.

EXAMPLE 10

A mixture of 22 g. of methyl 6-fluoro-2-naphthylacetate, 10 g. of sodiummethoxide, 6 g. of paraformaldehyde, and 200 ml. of dimethylsulfoxide isstirred for 18 hours at 25° C; the reaction mixture is acidified by theaddition of 250 ml. of 1N hydrochloric acid and extracted with methylenechloride. The extracts are combined, washed, dried, filtered, andevaporated to yield a mixture of methyl6-fluoro-2-naphthyl-α,α-methyleneacetate and methyl6-fluoro-2-naphthyl-α-hydroxymethylacetate. The two products areseparated by chromatographing on alumina, eluting with methanol-diethylether; the fractions are identified by ultraviolet spectroscopy.

Similarly, other 2naphthyl-α,α-methyleneacetic acid ester derivativesare prepared from the corresponding 2-naphthylacetic acid esterderivatives.

EXAMPLE 11

A mixture of 23 g. of methyl6-methyl-2-naphthalene-α,α-methyleneacetate, 23 g. of diiodomethane,19.6 g. of zinc-copper couple (comprising 19.5 g. of zinc and 0.1 g. ofcopper) and 500 ml. of diethyl either is refluxed for 6 hours and thencooled and filtered. The filtrate is washed with 0.1N hydrochloric acid,washed with water to neutrality, dried, and evaporated to yield methyl6-methyl-2-naphthyl-α,α-ethyleneacetate.

Similarly, other 2-naphthyl-α,α-ethyleneacetic acid ester derivativesare prepared from the corresponding 2-naphthyl-α,α-methyleneacetic acidester derivatives. Thus, methyl6,7-dimethoxy-2-naphthyl-α,α-ethyleneacetate is prepared from methyl6,7-dimethoxy-2-naphthyl-α,α-methyleneacetate.

EXAMPLE 12 Part A

A mixture of 24.4 g. of ethyl 6methoxy-2-naphthylacetate, 2.4 g. ofsodium hydride, and 100 ml. of diethyl carbonate is stirred for fourhours at 20° C. The product, diethyl 6-methoxy-2-naphthylmalonate(isolated by methylene chloride extraction), is added to 125 ml. of1,2-dimethoxyethane containing 33 g. of potassium tert-butoxide; themixture is allowed to stand for four hours at 60° C withchlorodifluoromethane being continually bubbled in after the mixture isinitially saturated. The mixture is carefully neutralized by theaddition of aqueous oxalic acid; the product, diethyl6-methoxy-2-naphthyl-α-difluoromethylacetate, is isolated by methylenechloride extraction and hydrolyzed by refluxing in 250 ml. of methanolcontaining 5 g. of potassium hydroxide and 5 ml. of water. The cooledmixture is acidified with oxalic acid and the product,6-methoxy-2-naphthyl-α-difluoromethylmalonic acid, is extracted withmethylene chloride. The dried product is decarboxylated by heating to180° C for six hours to give 6-methoxy-2-naphthyl-α-difluoromethylaceticacid.

Similarly, the α-difluoromethyl derivatives of the following compoundsare prepared from the corresponding esters: 1-ethyl-2-naphthylaceticacid, 1-chloro-2-naphthylacetic acid, 1-methylthio-2-naphthylaceticacid, 1,6-dimethyl-2naphthylacetic acid, 4-isopropyl-2-naphthylaceticacid, 4-fluoro-2-naphthylacetic acid, 4-ethylthio-2-naphthylacetic acid,4methyl-6-methoxy-2-naphthylacetic acid,4-methoxy-6-chloro-2-naphthylacetic acid, 6-methyl-2-naphthylaceticacid, 6-isopropyl-2-naphthylacetic acid, 6-cyclopropyl-2-naphthylaceticacid, 6-trifluoromethyl-2-naphthylacetic acid,6-methoxy-2-naphthylacetic acid, 6-methylthio-2-naphthylacetic acid,7-fluoro-2-naphthylacetic acid, 7methylthio-2-naphthylacetic acid, b6,7-dimethyl-2-naphthylacetic acid, 6,7dichloro-2-naphthylacetic acid,6-methoxy-7-methyl-2-naphthylacetic acid, 8-ethyl-2-naphthylacetic acid,8-chloro-2-naphthylacetic acid, 8-ethylthio-2-naphthylacetic acid, and6,8-dimethoxy-2-naphthylacetic acid.

Part B

A mixture of 31.6 g. of diethyl 6-methoxy-2-naphthylmalonate, 2.4 g. ofsodium hydride, and 350 ml. of methanol is stirred for one hour; then 24g. of methyliodide are added and the resulting mixture is refluxed for 2hours. The cooled mixture is neutralized with aqueous oxalic acid. Theproduct, diethyl 6-methoxy-2-naphthyl-α-methylmalonate, is isolated,hydrolyzed, and decarboxylated by the means of the above describedprocesses to give 6-methoxy-2-naphthyl-α-methylacetic acid.

EXAMPLE 13

A mixture of 24.4 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate, 25g. of sodium metal, and 500 ml. of anhydrous iso-amyl alcohol arerefluxed for 18 hours. The cooled reaction mixture is acidified by theaddition of aqueous 1N hydrochloric acid. The product is isolated bydiethyl ether extraction to give methyl6-methoxy-3,4-dihydro-2-naphthyl-α-methylacetate.

Similarly, methyl 1-methyl-3,4-dihydro-2-naphthylacetate, methyl1-fluoro-3,4-dihydro-2-naphthylacetate, methyl1-isopropoxy-3,4-dihydro-2-naphthylacetate, methyl1,6-dimethoxy-3,4-dihydro-2-naphthyl-α-methylacetate, methyl1-ethyl-3,4-dihydro-2-naphthylacetate, methyl7-chloro-3,4-dihydro-2-naphthyl-α-methylacetate, methyl7-methylthio-6-fluoro-3,4-dihydro-2-naphthylacetate, methyl6,7-dimethoxy-3,4-dihydro-2-naphthyl-α-ethylacetate, methyl6-methyl-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-fluoro-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-isopropyl-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-chloro-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-methylthio-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-trifluoromethyl-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-difluoromethoxy-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-methoxy-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-methoxymethyloxy-3,4-dihydro-2-naphthyl-α-difluoromethylacetate,methyl 6methylthio-3,4-dihydro-2-naphthylacetate, methyl7-methoxymethylthio-3,4-dihydro-2-naphthylacetate, methyl7-isopropyl-3,4-dihydro-2-naphthyl-α-methylacetate, methyl7-trifluoromethyl-3,4-dihydro-2-naphthylacetate, methyl7-ethoxy-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6,7-dimethyl-3,4-dihydro-2-naphthyl-α-ethylacetate, methyl6-fluoro-7-chloro-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6-methoxy-7-fluoro-3,4-dihydro-2-naphthylacetate, methyl8-methyl-3,4dihydro-2-naphthyl-α-methylacetate, methyl8-methoxy-3,4-dihydro-2-naphthyl-α-methylacetate, methyl6,8-difluoro-3,4-dihydro-2-naphthylacetate, and methyl6-methyl-8-methylthio-3,4-dihydro-2-naphthylacetate are prepared fromthe corresponding 2-naphthylacetic acid ester derivatives by means ofthe above process.

EXAMPLE 14 Part A

A mixture of 26 g. of methyl 6-methylthio-2-naphthyl-α-methylacetate,200 ml. of glacial acetic acid, and 2 ml. of 48% hydrobromic acid arerefluxed for 2 hours. The mixture is diluted with one liter of water andextracted with methyl chloride. The extracts are combined, washed withwater, dried over sodium sulfate, filtered, and evaporated to yield6-methyl-6-thio-2-naphthyl-α-methylacetic acid.

Part B

The above product is added to a mixture of 150 ml. of dioxane and 150ml. of aqueous 20% sodium hydroxide. The resulting mixture is heated to65° C and saturated with chlorodifluoromethane. The resulting mixture isallowed to stand for 2 hours while continuously bubbling inchlorodifluoromethane. The cooled reaction mixture is then acidified bythe addition of aqueous 1N hydrochloric acid and extracted with diethylether. The extracts are combined, washed with water to neutrality, driedover sodium sulfate, filtered, and evaporated to yield methyl6difluoromethylthio-2naphthyl-α-methylacetate.

Similarly, methyl 1-difluoromethoxy-2-naphthylacetate, methyl8-difluoromethoxy-2-naphthylacetate, methyl6-difluoromethoxy-2-naphthylacetate, methyl6-difluoromethoxy-3,4-dihydro-2-naphthylacetate, methyl7-trifluoromethylthio-2-naphthylacetate, methyl6-difluoromethylthio-2-naphthylacetate, methyl4-difluoromethylthio-2-naphthylacetate, methyl6,7-bis(difluoromethoxy)-2-naphthylacetate, methyl6-difluoromethoxy-2-naphthyl-α-methylacetate, methyl7-difluoromethoxy-2-naphthyl-α-methylacetate, methyl1-difluoromethoxy-6-difluromethylthio-2-naphthyl-α-methylacetate, methyl6-difluoromethoxy-8-chloro-2-naphthyl-α-difluoromethylacetate, methyl4-difluoromethylthio-6-methoxy-2-naphthyl-α,α-methyleneacetate, methyl8-difluoromethoxy-3,4-dihydro-2-naphthyl-α,α-difluoromethyleneacetate,methyl 6-difluoromethylthio-1-methoxy-2-naphthyl-α-ethylacetate areprepared from the corresponding 2-naphthylacetic acid ester derivativesby means of the above process.

EXAMPLE 15

A mixture of 23 g. of methyl 6-hydroxy-2naphthyl-α-methylacetate,methylacetate, 25 g. of chlorodimethyl ether, and 500 ml. ofdimethylformamide is allowed to stand at room temperature for 12 hours.The reaction mixture is evaporated under reduced pressure to give methyl6-methoxymethyloxy-2-naphthyl-α-methylacetate.

Methyl 6-isopropoxymethyloxy-2-naphthyl-α-methylacetate and methyl6-methylthiomethyloxy-2-naphthyl-α-methylacetate are similarly preparedby utilizing chloromethyl isopropyl ether and methylthio chloromethane,respectively, in place of chlorodimethyl ether in the above process.

Methyl 6-methoxymethylthio-2-naphthyl-α-methylacetate is prepared byutilizing methyl 6-thio-2-naphthyl-α-methylacetate in the above process.Likewise, methyl 6-methylthiomethylthio is prepared by using methyl6-thio-2-naphthyl-α-methylacetate and methylthio chloromethane in theprocess described above.

Likewise, methyl 1-methoxymethyloxy-2-naphthylacetate, methyl4,6-di(methoxymethyloxy)-2-naphthyl-α-methylacetate, methyl1-methoxy-6-methoxymethyloxy-2-naphthyl-α,α-methyleneacetate, methyl6,7-di(methoxymethylthio)-2-naphthyl-α-methylacetate, methyl8-ethoxymethylthio-3,4-dihydro-2-naphthylacetate, methyl4-ethoxymethyloxy-3,4-dihydro-2-naphthyl-α, α-difluoromethyleneacetate,methyl 6-methoxymethyloxy-3,4-dihydro-2-naphthyl-α-methylacetate, andmethyl 7-methoxymethyloxy-2-naphthyl-α-difluoromethylacetate areprepared from the corresponding 2-naphthylacetic acid derivatives bymeans of the above process.

EXAMPLE 16 Part A

A mixture of 500 ml. of benzene and 25 g. of 4-methoxy-2,6-dihydropyranis dried by distilling off 50 ml. To the remaining cooled mixture, 2 g.of para-toluene sulfonyl chloride and 26.6 g. of methyl6-hydroxy-2-naphthyl-α-difluoromethylacetate are added; the resultingmixture is stirred for 24 hours at 25° C. The mixture is neutralized bythe addition of aqueous 5% sodium bicarbonate. The resulting mixture isextracted with methylacetate. The extracts are combined, washed withwater, dried over sodium sulfate, filtered, and evaporated to givemethyl6-(4'-methoxytetrahydropyran-4'-yloxy)-2-naphthyl-α-difluoromethylacetate.

Similarly, methyl6-tetrahydropyran-2'-yloxy-2-naphthyl-α-difluoromethylacetate isprepared by using dihydropyran in place of 4-methyloxydihydropyran inthe above process.

Part B

A mixture of 22.8 g. of methyl4-hydroxy-2-naphthyl-α,α-methyleneacetate, 100 g. oftetrahydrofuran-2'-yl benzoate, and 500 ml. of benzene are refluxed for24 hours. The reaction mixture is distilled and the highest boilingfraction is collected to give methyl4-tetrahydrofuran-2'-yloxy-2-naphthyl-α,α-methyleneacetate.

Similarly, methyl6,8-bistetrahydrofuran-2'-yloxy-2-naphthyl-α-fluoroacetate is preparedfrom methyl 6,8-dihydro-2-naphthyl-α-fluoroacetate.

EXAMPLE 17

Chlorine gas is bubbled through a mixture of 23 g. of methyl6-methyl-2-naphthyl-α-methylacetate and 1 g. of phosphorus pentachloridein 200 ml. of carbon tetrachloride in the presence of light until 21.3g. of chlorine have been taken up. The reaction mixture is diluted with200 ml. of pyridine, filtered, further diluted with 500 ml. of ether,washed with water to neutrality, dried over sodium sulfate, andevaporated to yield methyl 6-trichloromethyl-2-naphthyl-α-methylacetate.The above product is then refluxed in a mixture of 500 ml. ofchlorobenzene and 17.9 g. of antimonytrifluoride. The cooled reactionmixture is washed with water, dried over sodium sulfate, and evaporatedto yield methyl 6-trifluoromethyl-2-naphthyl-α-methylacetate.

Similarly, methyl 8-trifluoromethyl-2-naphthylacetate, methyl1-methoxy-6-trifluoromethyl-2-naphthyl-α-ethylacetate, methyl6-trifluoromethyl-2-naphthylacetate, methyl6-trifluoromethyl-2-naphthyl-α,α-methyleneacetate, methyl4-fluoro-6-trifluoromethyl-2-naphthyl-α,α-methyleneacetate, methyl7-trifluoromethyl-2-naphthyl-α-methylacetate, methyl4,6-trifluoromethyl-2-naphthylacetate, methyl1-trifluoromethyl-3,4-dihydro-2-naphthyl-α-methylacetate, and methyl6-trifluoromethyl-2-naphthyl-α-difluoromethylacetate are prepared fromthe corresponding methyl substituted 2-naphthylacetic acid esterderivatives by means of the above process.

Example 18 Part A

A mixture of 24.2 g. of methyl 6-ethyl-2-naphthyl-α-methylacetate, 17.8g. of N-bromosuccinimide, and 10 mg. of benzoylperoxide, and 300 ml. ofchloroform are refluxed for two hours in the presence of light. Themixture is filtered and evaporated. The residue is heated in 200 ml. ofglacial acetic acid containing 16 g. of sodium acetate at 60° C for 24hours. Five hundred milliliters of water are added to the resultingmixture and the product is extracted by diethyl ether extractions. Theproduct, methyl 6-(α-acetoxyethyl)-2-naphthyl-α-methylacetate, ishydrolyzed by adding it to a 5% aqueous sodium carbonate solution. Theproduct, 6-(α-hydroxyethyl)-2-naphthyl-α-methylacetate, is isolated bydiethyl ether extractions. The isolated product is oxidized by adding itto 200 ml. of glacial acetic acid containing 25 g. of chromium trioxide.The resulting mixture is allowed to stand at room temperature for 1hour. Two hundred milliliters of a 10% sodium bisulfite solution areadded and the mixture is extracted with diethyl ether. The extracts arecombined, washed with water to neutrality, dried over sodium sulfate,filtered, and evaporated to givemethyl-6-acetyl-2-naphthyl-α-methylacetate.

Part B

To a mixture of 24 g. of 6-acetyl-2-naphthyl-α-methylacetic acid and 200ml. of diethyl ether are added 4.2 g. of diazomethane in 100 ml. ofdiethyl ether. The resulting mixture is evaporated to give methyl6-acetyl-2-naphthyl-α-methylacetate. The product is added to 200 ml. ofaqueous 20% sodium hypochlorite. The resulting mixture is allowed tostand for four hours at room temperature. The mixture is acidified bythe addition of aqueous 1N hydrochloric acid and extracted with diethylether. The extracts are combined, washed with water to neutrality, driedover sodium sulfate, filtered, and evaporated to give6-carboxy-2-napthyl-60 -methylacetic acid.

Part C

The above product is etherified with 8.4 g. of diazomethane by theprocedure described in Part B above to give methyl6-methoxycarbonyl-2-naphthyl-α-methylacetate. The diester is hydrolyzedby refluxing in 200 ml. of ethyl alcohol containing 4g. (one molarequivalent) of sodium hydroxide for 5 hours. The cooled mixture isacidified by the addition of aqueous 1N hydrochloric acid and theproduct is isolated by methylenechloride extraction to give6-methoxycarbonyl-2-naphthyl-α-methylacetic acid.

Part D

A mixture of 25.8 g. of 6-methoxycarbonyl-2-naphthyl-α-methylaceticacid, 4 g. of sodium hydroxide, 10 ml. of water, and 500 ml. of methanolare heated to 50° C, cooled and evaporated. The residue is taken up in500 ml. of diethylene glycol diemthyl ether and diborane is bubbledthrough. The resulting mixture is saturated with diborane and then isallowed to stand for 18 hours. The reaction mixture is acidified by theaddition of aqueous 1N hydrochloric acid. The mixture is extracted withmethylene chloride. The extracts are combined, washed with water toneutrality, dried over sodium sulfate, filtered, and evaporated to give6-hydroxymethyl-2-naphthyl-α-methylacetic acid.

Part E

A mixture of 23 g. of 6-hydroxymethyl-2-naphthyl-α-methylacetic acid,230 g. of manganese dioxide, and 2 l. of chloroform are stirred for 12hours; the mixture is filtered and evaporated to give6-formyl-2-naphthyl-α-methylacetic acid.

Part F

A mixture of 22.8 g. of 6-formyl-2-naphthyl-α-methylacetic acid, 14 g.of hydroxylamine hydrochloride, 25 g. of sodium acetate, and 1 l. ofethyl alcohol are refluxed for one hour; the cooled reaction mixture isdiluted with 1 l. of water and extracted with methylene chloride. Theextracts are combined, washed with water to neutrality, dried oversodium sulfate, filtered, and evaporated to give the oxime of6-formyl-2-naphthyl-α-methylacetic acid. The above oxime is refluxed in1 l. of acetic anhydride containing 20 g. of p-toluenesulfonic acid for1 hour; the reaction mixture is then evaporated to dryness. The residueis taken up in methylene chloride, washed with water, dried over sodiumsulfate, filtered, and evaporated to yield6-cyano-2-naphthyl-α-methylacetic acid.

Similarly, by means of the above processes,6-acetyl-2-naphthyl-α-difluoromethylacetic acid,6-carboxy-2-naphthyl-α-difluoromethylacetic acid,6-methyoxycarbonyl-2-naphthyl-α-difluoromethylacetic acid,6-hydroxymethyl-2-naphthyl-α-difluoromethylacetic acid,6-formyl-2-naphthyl-α-difluoromethylacetic acid, and the oxime thereof,and 6-cyano-2-naphthyl-α-difluoromethylacetic acid are prepared frommethyl 6-ethyl-2-naphthyl-α-difluoromethylacetate.

By utilizing diazoethane or 2-diazopropane in place of diazomethane inthe process of Part C, 6-ethoxycarbonyl-2-naphthyl-α-methylacetic acidor 6-isopropylcarbonyl-2-naphthyl-α-methylacetic acid are obtained.

Part G

A mixture of 5 g. of 6-carboxy-2-naphthyl-α-methylacetic acid, 2 ml. ofconcentrated hydrochloric acid, and 250 ml. of methanol are refluxed for10 minutes. The cooled mixture is evaporated to yield a mixture of6-methoxycarbonyl-2-naphthyl-α-methylacetic acid, methyl6-carboxy-2-naphthyl-α-methylacetate, and methyl6-methoxycarbonyl-2-naphthyl-α-methylacetate. The mixture is separatedby distillation and chromatography on alumina eluting with ether. Theseparated products are identified by nuclear magnetic resonancespectroscopy.

Part H

To a mixture of 24.4 g. of methyl6-hydroxymethyl-2-naphthyl-α-methylacetate (prepared from6-hydroxymethyl-2-naphthyl-α-methylacetic acid by esterifying the latterby means of the procedure described in Part A of this example) and 500ml. of benzene are added 2.4 g. of sodium hydride. The resulting mixtureis stirred for 2 hours; then 12.2 g. of methyliodide are added. Theresulting mixture is next neutralized by the addition of aqueous 1Nhydrochloric acid after it has been allowed to stand for one hour; themixture is then washed with water, dried over sodium sulfate, andevaporated to give methyl 6-methoxymethyl-2-naphthyl-α-methylacetate.

Methyl 6-ethoxymethyl-2-naphthyl-α-methylacetate is prepared by using13.7 g. of ethyliodide in place of methyliodide in the above process.

Example 19

To a mixture of 20 g. of sodium hydroxide and 400 ml. of methanol areadded 24.5 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate. Theresulting reaction mixture is heated to 60° C for 5 hours. The cooledmixture is neutralized by the addition of aqueous 1N hydrochloric acidand extracted with methylene chloride. The extracts are combined, washedwith water to neutrality, dried over sodium sulfate, filtered, andevaporated to give 6-methoxy-2-naphthyl-α-methylacetic acid.

Similarly, the other 2-naphthylacetic acid ester derivatives prepared bymeans of the procedures described in the other examples herein arehydrolyzed to the corresponding 2-naphthylacetic acid derivatives.

Example 20

A suspension of 2.4 g. of sodium hydride and 50 ml. of benzene is addedto a mixture of 23 g. of 6-fluoro-2-naphthyl-α-methylacetic acid and 450ml. of benzene. The resulting mixture is stirred for 4 hours. Themixture is cooled to 0° C and 19 g. of oxalyl chloride are added; afterthe addition, the mixture is allowed to stand for 4 hours. The resultingmixture is then saturated with ammonia and allowed to stand for eighthours. This mixture is then evaporated under reduced pressure. Theresidue is taken up in methylene chloride, washed with waater toneutrality, dried, filtered, and evaporated to give6-fluoro-2-naphthyl-α-methylacetamide.

Similarly, N-methyl-6-fluoro-2-naphthyl-α-methylacetamide,N,N-dimethyl-6-fluoro-2-naphthyl-α-methylacetamide,N-ethyl-6-fluoro-2-naphthyl-α-methylacetamide,N,N-diethyl-6-fluoro-2-naphthyl-α-methylacetamide,6-fluoro-2-naphthyl-α-methyl N-acetyl pyrrolidine,6-fluoro-2-naphthyl-α-methyl N-acetyl piperidine,6-fluoro-2-naphthyl-α-methyl N-acetyl morpholine,6-fluoro-2-naphthyl-α-methyl N-acetyl piperazine,6-fluoro-2-naphthyl-α-methyl N-acetyl-4'-methylpiperazine are preparedby means of the above process by replacing ammonia with methylamine,dimethylamine, ethylamine, diethylamine, pyrrolidine, piperidine,morpholine, piperazine, and 1-ethylpiperazine, respectively.

By means of the above process, the corresponding amides of the other2-naphthylacetic acid derivatives made by means described herein areprepared. Accordingly, 6-methyl-2-naphthylacetamide is prepared from6-methyl-2-naphthylacetic acid.

EXAMPLE 21

To a solution of 26 g. of 6-methoxymethyloxy-2-naphthyl-α-methylaceticacid and 500 ml. of diethyl ether are slowly added a solution comprisingof 5.6 g. of diazoethane and 50 ml. of diethyl ether. The reactionmixture is allowed to stand for 15 minutes and then is evaporated underreduced pressure to yield ethyl6-methoxymethyloxy-2-naphthyl-α-methylacetate. By replacing diazoethanewith diazopropane in the above process, propyl6-methoxymethyloxy-2-naphthyl-α-methylacetate is obtained.

By means of the above described process, the other 2-naphthylacetic acidderivatives made by the procedures described in the examples herein areesterified.

EXAMPLE 22

A mixture of 32 g. of methyl6-difluoromethoxy-2-naphthyl-α-difluoromethylacetate, 10 g. of sodiummethoxide, 14 g. of hydroxylamine hydrochloride, and 500 ml. of methanolare allowed to stand for 16 hours. The mixture is then filtered andevaporated. The residue is neutralized by the addition of aqueous 1Nhydrochloric acid and extracted by ether. The ether solution is thenwashed with water, dried, and evaporated to afford6-difluoromethoxy-2-naphthyl-α-difluoromethyl acethydroxamic acid.

Similarly, 6-methyl-2-naphthyl-α-methyl acethydroxamic is made by meansof the above process from methyl 6-methyl-2-naphthyl-α-methyl acid.

Similarly, the corresponding hydroxamic acids of the other2-naphthylacetic acid derivatives prepared via the procedures describedin the examples herein are made by means of the above described process.

EXAMPLE 23

To a mixture of 4 g. of sodium hydroxide and 500 ml. of methanol areadded 24.6 g. of 6-methylthio-2-naphthyl-α-methylacetic acid. Themixture is stirred for 18 hours at 50° C. The cooled mixture is thenevaporated to give sodium 6-methylthio-2-naphthyl-α-methylacetate.

By employing potassium hydroxide, diethylamine, lysine, caffeine, orprocaine in place of sodium hydroxide in the above process, thepotassium triethylamine, lysine, caffeine, or procaine salt of6-methylthio-2-naphthyl-α-methylacetic acid is obtained.

By means of the above procedure, the addition salts of the other2-naphthylacetic acid derivatives made via the procedures describedherein are prepared.

EXAMPLE 24

A mixture of 2.2 g. of 6-hydroxy-2-naphthyl-α-methylacetic acid, 50 ml.of acetic anhydride, and 100 mg. of p-toluenesulfonic acid is stirredfor four hours at 50° C. The mixture is evaporated, water is added, andthe mixture is extracted with diethyl ether which is washed with waterto neutrality, dried over sodium sulfate, and evaporated to yield6-acetoxy-2-naphthyl-α-methylacetic acid.

Methyl 6-acetoxy-2-naphthyl-α-methylacetate is prepared from the aboveproduct by means of the esterification procedure described in Example21.

EXAMPLE 25

A mixture of 2.3 g. of 6-methoxy-2-naphthyl-α-methylacetic acid, 2.9 g.of cinchonidine, and 50 ml. of methanol is stirred for 2 hours; themixture is then allowed to stand until crystallization is complete. Thecrystals are filtered off and washed with methanol. The crystals arerecrystallized from methanol, filtered, washed, and dried. The purecrystals are added to 60 ml. of 0.2N hydrochloric acid. The resultingmixture is stirred for two hours and then extracted with diethyl ether.The extracts are combined, washed with water to neutrality, dried oversodium sulfate, and evaporated to yield one of the optical isomers of a6-methoxy-2-naphthyl-α-methylacetic acid. The filtrates from the abovefiltrations are acidified with aqueous dilute hydrochloric acid and theproduct is isolated by diethyl ether extractions to give the otheroptical isomer of 6-methoxy-2-naphthyl-α-methylacetic acid.

Similarly, the optical isomers of the other α-mono-substituted2-naphthylacetic acid derivatives made via the procedures describedherein are separated.

EXAMPLE 26

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        2-naphthylacetic acid                                                                            50                                                         cornstarch        200                                                         ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets, one tablet being administered every three to four hours.

EXAMPLE 27

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        6-methoxy-2-naphthyl-                                                         α-methylacetic acid                                                                        30                                                         cornstarch        100                                                         lactose           370                                                         Magnesium stearate                                                                               2                                                          ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 28

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        6-methylthio-2-naphth-                                                        yl-α-methylacetic acid                                                                     25                                                         lactose           225                                                         ______________________________________                                    

The above ingredients are mixed and introduced into a No. 1 hard-shellgelatin capsule.

In a similar manner as that described in each of the preceding threeexamples, the following compounds can also be so formulated:6-methoxy-2-naphthyl-α-methylacetic acid,6-methylthio-2-naphthyl-α-methylacetic acid,6-chloro-2-naphthyl-α-methylacetic acid,6-fluoro-2-naphthyl-α-methylacetic acid,6-methyl-2-naphthyl-α-methylacetic acid,6-trifluoromethyl-2-naphthyl-α-methylacetic acid,6-difluoromethoxy-2-naphthyl-α-methylacetic acid,6-chloro-2-naphthylacetic acid, 6-methylthio-2-naphthylacetic acid,6-methyl-2-naphthylacetic acid, 4-chloro-2-naphthylacetic acid,3,4-dihydro-6-methoxy-2-naphthyl-α-methylacetic acid,3,4-dihydro-6-methylthio-2-naphthyl-α-methylacetic acid,3,4-dihydro-6-chloro-2-naphthyl-α-methylacetic acid,1-methyl-2-naphthyl-α,α-methyleneacetic acid, sodium8-chloro-2-naphthyl-α-fluoroacetate, methyl6,7-dimethylthio-2-naphthylacetate,4-methylthiomethyleneoxy-2-naphthyl-α-difluoromethylacetic acid,4-methyl-2-naphthylacetic acid,1-methoxy-6-(4'-methoxytetrahydropyran-4'-yloxy)-2-naphthylacetamide,potassium 3,4-dihydro-7-methyl-2-naphthyl-α,α-difluoromethyleneacetate,3,4-dihydro-6-fluoro-2-naphthyl-α-methylacetic acid,3,4-dihydro-6-methyl-2-naphthyl-α-methylacetic acid,3,4-dihydro-6-difluoromethoxy-2-naphthyl-α-methylacetic acid,3,4-dihydro-6-methoxy-2-naphthylacetic acid,3,4-dihydro-6-methylthio-2-naphthylacetic acid,3,4-dihydro-6-chloro-2-naphthylacetic acid,3,4-dihydro-6-methyl-2-naphthylacetic acid, N,N-diethyl4-isopropyl-2-naphthyl-α-methylacetamide, and the like.

What is claimed is:
 1. A compound of the formula ##STR9## wherein: R⁷ ismethyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl,fluoro, or chloro;one of R¹⁰ and R¹¹ is hydrogen, the other being methylor difluoromethyl or R¹⁰ and R¹¹ taken together are methylene ordifluoromethylene; and the corresponding alkyl esters of 1-12 carbonatoms and pharmaceutically acceptable acid addition salts thereof. 2.The compound of formula XIV according to claim 1 wherein R⁷ is methyl;one of R¹⁰ and R¹¹ is hydrogen and the other is methyl.
 3. The compoundof formula XIV according to claim 1 wherein R⁷ is ethyl; one of R¹⁰ andR¹¹ is hydrogen and the other is methyl.
 4. The compound of formula XIVaccording to claim 1 wherein R⁷ is trifluoromethyl; one of R¹⁰ and R¹¹is hydrogen and the other is methyl.
 5. The compound of formula XIVaccording to claim 1 wherein R⁷ is fluoro; one of R¹⁰ and R¹¹ ishydrogen and the other is methyl.
 6. The compound of formula XIVaccording to claim 1 wherein R⁷ is chloro; one of R¹⁰ and R¹¹ ishydrogen and the other is methyl.